2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Vineet Bhandari, MD, DM
Professor of Pediatrics, Obstetrics and Gynecology
Pediarics (Neonatology)
Office Location
NCB, Suite #7410
Phone Number
215-762-7595
E-mail
vinet.bhandari@drexelmed.edu
Amount of time you are available for direct student supervision:
At least 3 days a week.
Any specific skills required:
Some basic knowledge of molecular biology techniques (RNA, protein extraction and detection by PCR, western blotting)
would be useful
Project Information:
Project Name
Role of hyperoxia-induced injury in developing lungs and brain.
Project DescriptionRU$UHDRI,QWHUHVW
Our research laboratory is interested in understanding the pathogenesis of hyperoxia-induced injury to the developing lung and
brain in order to develop therapeutic targets to ameliorate the same. The clinically-relevant condition(s) would be
Bronchopulmonary Dysplasia in the premature neonate, and its association with developmental delay.
Our lab uses transgenic and knockout mice models to study the above, in addition to in vitro work, utilizing molecular biology
techniques to conduct the experimental studies.
Currently we are focused on understanding the role of various micro-RNA, ion channels and mesenchymal stem cells in
modulating the pulmonary and brain phenotype in neonatal mice exposed to hyperoxia.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Wilbur B. Bowne, MD
Associate Professor of Surgery, Biochemistry, and Molecular Biology
Surgery
Office Location
245 N 15th Street (NCB), Suite 7150
Phone Number
215-762-1647
E-mail
wilbur.bowne@drexelmed.edu
Amount of time you are available for direct student supervision:
15 hours per week - 2 postdoctoral research fellows (Surgical residents) will also be present in the lab.
Any specific skills required:
Previous experience with cell cultures or with rodents preferred but not required.
Project Information:
Project Name
Targeting MDM-2 overexpression in human stem-like and mature colon cancer cells as an anti-cancer therapy for treatment of
peritoneal carcinomatosis
Project Description or Area of Interest
Peritoneal carcinomatosis (PC) from pancreatic, colon and gastric cancer represents a grim prognosis for patients. Novel
therapies are sorely needed to provide effective treatment strategies for these patients. Recent studies have shown that tumorspecific cancer stem cells may be the cause of drug resistance, local recurrence, and the earliest signs of metastasis. Our
laboratory is focused on developing anticancer drugs that selectively target and kill cancer cells, with the hypothesis that these
therapies will eliminate CSCs as well. Two such drugs discovered in our laboratory called PNC-27 and PNC-28 are derived
from the murine-double-minute (MDM-2) protein binding domain of p53 attached to a membrane penetrating sequence, called
penetratin. These peptide constructs have been shown to induce rapid, targeted, cancer cell necrosis by binding to MDM2 on
the cancer cell membrane causing pore-formation and cancer membrane cell lysis. Remarkably, PNC-27 has been shown to
efficiently kill cancer cells while sparing untransformed cells. Thus, this peptide may prove to be an effective targeted treatment
strategy for patients with lethal PC. Our laboratory ihas shown the effectiveness of this peptide in treatment of colon cancer
peritoneal carcinomatosis in a nude mouse xenograft model using real-time in-vivo bioluminescence imaging. This strategy
will be used in our preclinical studies to determine the treatment efficacy of these peptides against lethal peritoneal surface
malignancies and colon cancer stem cells.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Tara Davis, Ph.D. & Sandhya Kortagere, Ph.D.
Assistant Professor; Associate Professor
Biochemistry & Molecular Biology, Microbiology & Immunology
Office Location
245 North 15th Street, M.S. 497/Lab 10.127; G81
Phone Number
215-762-4234 (office) / 215-762-4218 (lab), 215-991-8135
E-mail
tara.davis@drexelmed.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
Project Information:
Project Name
Project Description or Area of Interest
Purpose: Drs. Davis and Kortagere are collaborating on a research program focused on the design of unique and novel small
molecules to target a class of human enzyme called the cyclophilins. Individual projects within this program target individual
cyclophilins; there are 17 cyclophilins in humans, and many are viable drug targets, including some that could lead to eventual
anti-viral or anti-cancer drugs. Other projects focus on cyclophilins whose function is less well understood, and where small
molecules may help to decode their particular activities within the cell. Historically, efforts to screen for new inhibitors of
cyclophilin activity have been hampered by the high similarity of cyclophilin proteins to each other; our effort uses
high-resolution structures of the cyclophilin family to guide structure-based screening of thousands of compounds to find
unique small molecules targeting each cyclophilin.
Goals: Dr. Kortagere is an expert in the design of small molecules to target biologically relevant protein targets
(https://www.drexelmed.edu/Home/AboutOurFaculty/SandhyaKortagere.aspx). Dr. Davis is an expert in cyclophilin function,
and an x-ray crystallographer - a technique commonly used to study protein structure
(https://www.drexelmed.edu/Home/AboutOurFaculty/TaraDavis.aspx). Students interested in the research program will spend
time in both labs, benefitting from the experience of both Professors. As outlined in greater detail below, students successfully
completing the co-op experience can be expected to have basic competency in:
• Foundational concepts surrounding protein structure, including how to visualize and manipulate protein and small molecule
structure using standard graphical software (PyMOL)
• Understanding of small molecule docking to protein structure in silico (AutoDock, GOLD)
• Protein purification using standard protocols, including large-scale production, multi-step purification utilizing affinity and
size exclusion chromatography
• Biophysical methods to measure small molecule binding to protein, including Surface Plasmon Resonance (SPR) and/or
Isothermal Calorimetry (ITC)
• Protein crystallization, crystal harvesting and cryoprotection, in-house data collection
There are three aspects to this project; summer students will receive a truncated version of these goals for their project term.
Aspect 1: Student will commute to Center City Campus for training sessions with Dr. Davis. Students will be trained in the
basic concepts of protein structure, including reading assignments from textbooks (Chapters 3-4 of Lehninger, for example),
primary literature, and software tutorials. Much of this time will be spent learning how to visualize the three-dimensional
structure of human cyclophilins using PyMOL, along with tutorials on how to manipulate structure within PyMOL. Cyclophilin
activity and function will also be discussed.
Aspect 2: Student will commute to Queen Lane Campus for training sessions with Dr. Kortagere. Students will be trained to
dock small molecules of interest into individual cyclophilin structures. Students will be trained to use Autodock and/or GOLD
molecular docking programs and to dock small molecules to the binding pockets of cyclophilins. Students will then analyze the
docked models and learn to design customized scoring schemes to optimally rank the docked protein-ligand complexes. The
best ranking molecules will be synthesized or purchased from chemical libraries (10-15 compounds) in order to test with in
vitro experiments, including NMR and co-crystallization with the respective cyclophilins, to validate docked poses during
weeks 7-24. Students interested in pursuing in-depth analysis will also have the opportunity to run molecular dynamics
simulations (~100ns) on select few ligand-protein complexes.
Aspect 3: Experiments are performed at Center City Campus with Dr. Davis. Depending on the outcome of the docking
experiments in weeks 4-6, the student may learn a variety of various wet lab techniques, including:
• expression and purification of cyclophilin protein;
• quantifying the affinity of small molecule(s) for purified cyclophilin protein;
• crystallization of apo or liganded forms of cyclophilin;
• activity assays testing either cyclophilin isomerase activity, or RNA splicing modulation, for comparison to inhibitor-based
assays with small molecules;
• PCR-based protocols to produce mutant protein based on structural or enzymatic results;
• cell-based assays on human cells to measure effect of small molecule uptake on RNA splicing activity.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Tara Davis, PhD
Assistant Professor
Biochemistry & Molecular Biology
Office Location
245 North 15th Street, M.S. 497/Lab 10.127
Phone Number
215-762-4234 (office) / 215-762-4218 (lab)
E-mail
Tara.Davis@DrexelMed.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
N/A
Project Information:
Project Name
Project Description or Area of Interest
The Davis Lab studies the way in which protein:protein interactions impact the function of the spliceosomal machinery in the
context of pre-mRNA splicing. Many human disease pathologies arise from aberrations in pre-mRNA processing, which leads
to the expression of malfunctioning proteins in cells. Therefore there is a great and pressing need to better understand the
underlying mechanism of the spliceosome, the complex and dynamic machinery which accomplishes pre- mRNA splicing in
human cells. Although the spliceosome is a large and dynamic piece of macromolecular machinery, its cellular function and the
regulation of that function are likely mediated by individual protein:protein interactions between the hundreds of accessory
proteins that associate tightly with the core machinery composed of RNA. Therefore, understanding the nature of specific
protein:protein interactions will help us understand spliceosome assembly, catalysis, and splice choice – both within and
outside of the context of the machinery in cells.
Position Description (1):
The main responsibilities of the job include performing standard molecular biology and biochemical experiments under the
supervision of senior lab personnel; organizing and analyzing data in an electronic notebook format; and communicating
scientific results to supervisors and peers in both oral and written format. Prior laboratory experience is preferred but not
necessary. The desired candidate is dedicated, hard- working, organized, and inquisitive. Current projects focus on the
characterization of several proteins found in catalytic spliceosome (PPIL3, PCBP1, PPIG, and ZCCHC10). These proteins have
been found to interact with each other in yeast two-hybrid studies, but the behavior of the purified proteins in solution has not
been quantified. Major milestones of the project include optimizing expression and purification protocols for these proteins;
once optimized, their binding will be characterized in solution using chromatographic methods and quantified using biophysical
approaches. Crystallographic screening will be attempted in order to obtain structural information for the PPIL3:PCBP1 and/or
the PPIG:ZCCHC10 complexes. In a complementary set of experiments, these genes will be knocked down at the RNA level
using silencing RNA technology, and the physiological effect of these knockdowns will be evaluated using in vitro splicing
assays and at the transcriptome level using microarrays.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Megan R Detloff
Instructor
Neurobiology & Anatomy
Office Location
Queen Lane Room 184e
Phone Number
215-991-8286
E-mail
mdetloff@drexelmed.edu
Amount of time you are available for direct student supervision:
8 hr/week.
Any specific skills required:
Helpful to have experience handling rodents, experience with tissue sectioning and immunohistochemistry.
Project Information:
Project Name
Strength training to reduce nociceptive afferent plasticity and neuropathic pain after spinal cord injury
Project Description or Area of Interest
Spinal cord injury (SCI) impairs normal sensation causing chronic neuropathic pain in nearly 80% of people with SCI. One
type of neuropathic pain is allodynia, where normally innocuous stimuli are perceived as painful. That is, everyday activities
like wearing a t-shirt or being covered by a bed sheet is painful. It is a complex phenomenon that is refractive to treatment,
largely because the mechanism(s) responsible for its development and sustainment remain elusive.
There are four types of primary sensory neurons whose afferents synapse in the dorsal horn and transmit pain and sensory
information. These neuron classes are distinct in function, size, as well as where they terminate within the dorsal horn. There
are 4 classes of primary afferent fibers that terminate in the dorsal horn of the spinal cord: Ab fibers which transmit innocuous
sensory information terminating in laminae III and IV; Ad fibers which transmit noxious and innocuous information and
terminate in laminae I and V; peptidergic c-fibers which terminate in lamina I and the outer layer of lamina II; and
non-peptidergic c-fibers which terminate in the inner layer of lamina II. In addition, these classes of primary sensory neurons
exhibit distinct/unique molecular phenotype that may further define their functionality in the transmission of painful
information. That these different classes of primary sensory neurons have distinct molecular phenotypes, responding to
different factors and terminate in discrete spinal cord laminae suggests that they may play distinctive roles in sensory
transmission under normal as well as neuropathic conditions.
Dramatic, aberrant sprouting of peptidergic c-fibers into the deep dorsal horn occurs above, at and below the SCI epicenter in
clinical as well as experimental SCI. This sprouting correlates with an increase in the development of neuropathic pain. Our lab
has shown that SCI-induced mechanical allodynia is associated with an increase in the distribution of both peptidergic and
non-peptidergic c fibers, and that rehabilitative aerobic exercise can prevent this aberrant plasticity. Whether post-injury
strength training exercise will have similar effects is unknown. Therefore, we will test the hypothesis that rehabilitative strength
training will modulate nociceptive afferent plasticity while reducing the incidence of SCI-induced neuropathic pain.
This project will test whether strength training exercise will modify nociceptive afferent plasticity in the cervical dorsal horn
resulting in attenuated SCI-induced neuropathic pain. Experiments will use a unilateral C5 contusion model of spinal cord
injury paired with the isometric pull task as a novel strength training rehabilitation to test this hypothesis. A battery of
behavioral tests will determine the incidence of neuropathic pain. The distribution of nociceptive afferents in the dorsal horn
complimentary to the induction and persistence of pain will be established. This study is impactful because it could establish
strength training as an additional rehabilitative strategy to prevent SCI-induced pain.
Student role: Assist and perform microsurgical procedures, post-operative care of rodents, exercise training, behavioral
assessment of sensation in rodents, spinal cord and dorsal root ganglion tissue processing,lesion analysis, data analysis.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Eileen K. Jaffe
Adjunct Biochemistry Faculty at Fox Chase Cancer Center
Biochemistry and Molecular Biology
Office Location
Fox Chase Cancer Center
Phone Number
215 728-3695
E-mail
Eileen.Jaffe@fccc.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
Project Information:
Project Name
Optimizing crystallization conditions for determining the structure of phenylalanine-stabilized fully-activated phenylalanine
hydroxylase
Project Description or Area of Interest
Dysfunction of the enzyme phenylalanine hydroxylase (PAH) is the root cause of most forms of phenylketonuria (PKU) and/or
hyperphenylalaninemia (1, 2). PAH functions to maintain phenylalanine (Phe) at levels sufficient for the body’s need for
protein biosynthesis but below neurotoxic levels. This delicate control is accomplished by Phe acting as an activator of PAH in
response to a protein-containing meal. Despite the success of a protein-restrictive diet in preventing permanent neurological
damage in infants and children with PKU, there is a clear need for additional therapeutic measures to counteract the behavioral
and psychiatric problems associated with adolescents and adults who struggle with the necessary dietary restrictions (1). New
therapeutics can arise from a thorough understanding PAH structure.
In 2013 we described a novel structural paradigm for PAH activation by Phe, which consists of two different tetrameric PAH
conformations (3). One conformation represents an auto-inhibited enzyme form with basal activity, which is functional when
Phe levels are low. We have recently solved the X-ray crystal structure of this auto-inhibited tetrameric form (4), which
represents a major contribution to the field. The second tetramer represents the activated form of the enzyme, which is
stabilized by allosteric Phe binding when Phe levels are elevated. The goal of the proposed DUCOM medical student summer
fellowship project is to optimize crystallization conditions that will allow determination of the structure of the Phe-stabilized
activated PAH tetramer. Determining this structure will provide a long-needed target for structure-based design/discovery of
small-molecule therapeutics that can stabilize activated PAH to serve patients throughout life.
Our 2013 proposal for PAH regulation predicted that the activated PAH structure would relieve an autoinhibitory interaction
seen in our current crystal structure and would contain a new inter-subunit protein-protein interface that defines the location of
allosteric Phe binding. This new interface is a target for developing a drug that will stabilize activated PAH. Transformation
from the autoinhibited to the activated form is predicted to include significant repositioning of structural domains within each
subunit.
The medical student summer fellow would work closely with graduate student Emily Arturo to optimize crystallization
conditions in the presence of Phe. The laboratory already has copious amounts of purified full length mammalian PAH. The
search for suitable crystallization conditions is being carried out initially on a Mosquito robotic instrument using a variety of
commercial screening kits. Conditions will be optimized by making small systematic changes in the crystallization solutions.
In the event that promising crystals are obtained, the medical student may participate in screening these crystals for diffraction
quality. The medical student may also participate in harvesting the crystals to be mailed to Argonne National Laboratory for
remote data collection.
Alternative approaches – If necessary, alternative forms of PAH can be used to derive a crystal structure for the Phe-stabilized,
high-activity PAH tetramer. These forms include 1) an N-terminal truncation lacking the autoinhibitory peptide, 2) full-length
PAH that is phosphorylated at Ser16, or 3) a phosphomimic PAH variant S16E. It is possible that the medical student may
participate in the purification of these alternate forms of PAH.
References
1. Camp KM, et al. (2014) Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol
Genet Metab 112(2):87-122.
2. Blau N, Shen N, & Carducci C (2014) Molecular genetics and diagnosis of phenylketonuria: state of the art. Expert review of
molecular diagnostics 14(6):655-671.
3. Jaffe EK, Stith L, Lawrence SH, Andrake M, & Dunbrack RL, Jr. (2013) A new model for allosteric regulation of
phenylalanine hydroxylase: implications for disease and therapeutics. Arch Biochem Biophys 530(2):73-82.
4. Arturo E, et al. (2016) The First Structure of Full-Length Mammalian Phenylalanine Hydroxylase Reveals the Architecture
of an Auto-inhibited Tetramer. Revised manuscript under review by Proc. Natl. Acad. Sci.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Simon Giszter
Professor
Neurobiology and Anatomy
Office Location
247 Queen Lane
Phone Number
215 991 8412
E-mail
sgiszter@drexelmed.edu
Amount of time you are available for direct student supervision:
4 hours per week, with postdoctoral and senior graduate assistance at other times.
Any specific skills required:
Engineering or quantitative background, or neurophysiological experience
Project Information:
Project Name
Neural recording and neural plasticity in spinal cord and cortex in spinal cord injury, rehabilitation and BMI tasks
Project Description or Area of Interest
We seek to understand how cortex and spinal cord activity is altered by spinal cord injury, rehabilitation after spinal cord injury
and novel therapies such as brain machine interface devices. Our focus is on motor control in particular, and novel device
designs. Projects can be customized to match student focus and passions, subject to the main emphases and methods used in the
lab.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Haviva M. Goldman, Ph.D.
Associate Professor
Neurobiology and Anatomy
Office Location
Room 252 Queen Lane
Phone Number
215-991-8467
E-mail
hgoldman@drexelmed.edu
Amount of time you are available for direct student supervision:
I am around the lab/in my office most days for consultation/training.
Any specific skills required:
Experience with microscopy & image analysis is preferred, not required. Computer programming experience in Matlab also a
plus.
Project Information:
Project Name
Bone Remodeling, Morphology and Skeletal Fragility
Project Description or Area of Interest
Project: Skeletal fragility can be generalized as the skeleton’s increased susceptibility to fracture, which may be caused by poor
bone quality and/or quantity. Bone loss occurs throughout the aging process, and it may additionally be affected by numerous
variables, one of which may bone size. Previous research has demonstrated that a relationship exists between external bone size
and tissue level mechanical properties, such that more slender bones have increased mineralization and decreased porosity,
resulting in a higher tissue modulus relative to more robust individuals who tend to increase porosity in order to minimize mass.
We have hypothesized that this modulation reflects a suppression of intracortical (BMU based) remodeling in more slender
bones. This could lead to unrepaired microdamage in slender boned individuals and an increased skeletal fragility. Further, as
intracortical remodeling is a central biological process that occurs throughout growth and with aging, lifelong suppression of
remodeling would have significant effects on bone properties and fracture risk. The goal of this study is to quantify static
histomorphometric measures of bone turnover in adult cortical bone samples in order to determine the relationship between
bone robustness and intracortical remodeling.
The medical student involved in this project will learn about a variety of microscopy and imaging techniques used to
characterize the microstructural and geometric properties of bone. They will be specifically involved in analyzing 2D images
of bone structure in order to assess remodeling differences between slender and robust bone phenotypes.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Erica Golemis, Ph.D.
Co-Leader, Molecular Therapeutics Program, Fox Chase Cancer Center
Biochemistry & Molecular Biology
Office Location
Fox Chase Cancer Center, W406
Phone Number
215-728-2860
E-mail
erica.golemis@fccc.edu
Amount of time you are available for direct student supervision:
Available personally most of summer; senior staff available all summer for supervision.
Any specific skills required:
Experience with cell culture, molecular biological or biochemical experiments a plus
Project Information:
Project Name
1) Hereditary risk factors in kidney cancer.
2) Role of targeted cancer therapies in regulating cilia.
Project Description or Area of Interest
1) Hereditary risk factors in kidney cancer. We have been using exome sequencing coupled with cell culture based functional
testing to identify new factors contributing to familial risk for cancer. Recent evidence suggests that in some cases, kidney
cancer may arise from hereditary components, but in contrast to cancers such as prostate or breast cancer, risk factors are poorly
understood. We will be function testing new gene variants we have identified as potential sources of kidney cancer risk based
on exome sequencing, using and expanding approaches we have recently described. Relevant reading from our group is Arora
et al, Gastroenterology 2015 (PMID: 26344056) and Nicolas et al, Oncotarget 2015 (PMID: 26485759).
2) Role of targeted cancer therapies in regulating cilia. Most human cells have a single cilium, protruding like an antenna and
serving as a signaling hub. We and others have established that dynamic control of cilia during the cell cycle and in cell
transformation is regulated by oncogenes that serve as targets for current cancer therapies. Over 500,000 individuals in the US
suffer from ciliopathies (diseases such as polycystic kidney disease, linked to abnormal ciliary function). Our data suggests that
use of specific targeted cancer drugs in these patients may be extremely disfavored, due to exacerbation of symptoms. We will
be extending results from a large in vitro screen, characterizing means of ciliary control. Relevant reading from our group is
Pugacheva et al, Cell 2007 (PMID: 17604723), and Seeger-Nukpezah et al, Nat Rev Nephrol 2015 (PMID: 25870008).
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
John D Houle
Professor
Neurobioogy and Anatomy
Office Location
Queen Lane Room 184
Phone Number
215-991-8295
E-mail
jhoule@drexelmed.edu
Amount of time you are available for direct student supervision:
8-10 hrs each week
Any specific skills required:
Any of the following skills would be helpful for this study but are not required: immunocytochemistry, confocal microscopy,
cryostat sectioning.
Project Information:
Project Name
Axon regeneration after spinal cord injury: role of integrins in regulating growth within a peripheral nerve graft
Project Description or Area of Interest
Injury to the adult spinal cord results in limited regeneration of damaged central nervous system (CNS) axons and poor return
of function. This can be solved in part by providing an appropriate substrate for axon growth (such as a peripheral nerve graft,
PNG) which allows axons to bypass the inhibitory environment of the injured spinal cord. One issue though is the continuing
problem of how to facilitate or enhance axon growth back into the spinal cord to form new synaptic contacts. Axons readily
grow to the distal end of the PNG but the majority (~95%) fail to extend beyond the PNG to interact with spinal cord neurons.
Treatment of the injured spinal cord with an enzyme (chondroitinase) to digest inhibitory molecules (chondroitin sulfate
proteoglycans) of the extracellular matrix results in outgrowth by about 20% of regenerating axons within a PNG. Preliminary
data suggest that the physical/chemical interaction between axons and Schwann cells within the PNG may contribute to failure
of axons to extend back into the spinal cord. Particularly we are interested in defining the role of integrins in anchoring growing
axons to the laminin coating around Schwann cells, thereby limiting further growth.
The proposed summer project will be to use immunocytochemistry and confocal microscopy to examine the expression of axon
and Schwann cell specific integrins during different stages of axonal growth and to use specific inhibitors to disrupt the bond
between two as an approach to increase growth beyond the PNG.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Eileen K. Jaffe
Adjunct Biochemistry Faculty at Fox Chase Cancer Center
Biochemistry and Molecular Biology
Office Location
Fox Chase Cancer Center
Phone Number
215 728-3695
E-mail
Eileen.Jaffe@fccc.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
Project Information:
Project Name
Optimizing crystallization conditions for determining the structure of phenylalanine-stabilized fully-activated phenylalanine
hydroxylase
Project Description or Area of Interest
Dysfunction of the enzyme phenylalanine hydroxylase (PAH) is the root cause of most forms of phenylketonuria (PKU) and/or
hyperphenylalaninemia (1, 2). PAH functions to maintain phenylalanine (Phe) at levels sufficient for the body’s need for
protein biosynthesis but below neurotoxic levels. This delicate control is accomplished by Phe acting as an activator of PAH in
response to a protein-containing meal. Despite the success of a protein-restrictive diet in preventing permanent neurological
damage in infants and children with PKU, there is a clear need for additional therapeutic measures to counteract the behavioral
and psychiatric problems associated with adolescents and adults who struggle with the necessary dietary restrictions (1). New
therapeutics can arise from a thorough understanding PAH structure.
In 2013 we described a novel structural paradigm for PAH activation by Phe, which consists of two different tetrameric PAH
conformations (3). One conformation represents an auto-inhibited enzyme form with basal activity, which is functional when
Phe levels are low. We have recently solved the X-ray crystal structure of this auto-inhibited tetrameric form (4), which
represents a major contribution to the field. The second tetramer represents the activated form of the enzyme, which is
stabilized by allosteric Phe binding when Phe levels are elevated. The goal of the proposed DUCOM medical student summer
fellowship project is to optimize crystallization conditions that will allow determination of the structure of the Phe-stabilized
activated PAH tetramer. Determining this structure will provide a long-needed target for structure-based design/discovery of
small-molecule therapeutics that can stabilize activated PAH to serve patients throughout life.
Our 2013 proposal for PAH regulation predicted that the activated PAH structure would relieve an autoinhibitory interaction
seen in our current crystal structure and would contain a new inter-subunit protein-protein interface that defines the location of
allosteric Phe binding. This new interface is a target for developing a drug that will stabilize activated PAH. Transformation
from the autoinhibited to the activated form is predicted to include significant repositioning of structural domains within each
subunit.
The medical student summer fellow would work closely with graduate student Emily Arturo to optimize crystallization
conditions in the presence of Phe. The laboratory already has copious amounts of purified full length mammalian PAH. The
search for suitable crystallization conditions is being carried out initially on a Mosquito robotic instrument using a variety of
commercial screening kits. Conditions will be optimized by making small systematic changes in the crystallization solutions.
In the event that promising crystals are obtained, the medical student may participate in screening these crystals for diffraction
quality. The medical student may also participate in harvesting the crystals to be mailed to Argonne National Laboratory for
remote data collection.
Alternative approaches – If necessary, alternative forms of PAH can be used to derive a crystal structure for the Phe-stabilized,
high-activity PAH tetramer. These forms include 1) an N-terminal truncation lacking the autoinhibitory peptide, 2) full-length
PAH that is phosphorylated at Ser16, or 3) a phosphomimic PAH variant S16E. It is possible that the medical student may
participate in the purification of these alternate forms of PAH.
References
1. Camp KM, et al. (2014) Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol
Genet Metab 112(2):87-122.
2. Blau N, Shen N, & Carducci C (2014) Molecular genetics and diagnosis of phenylketonuria: state of the art. Expert review of
molecular diagnostics 14(6):655-671.
3. Jaffe EK, Stith L, Lawrence SH, Andrake M, & Dunbrack RL, Jr. (2013) A new model for allosteric regulation of
phenylalanine hydroxylase: implications for disease and therapeutics. Arch Biochem Biophys 530(2):73-82.
4. Arturo E, et al. (2016) The First Structure of Full-Length Mammalian Phenylalanine Hydroxylase Reveals the Architecture
of an Auto-inhibited Tetramer. Revised manuscript under review by Proc. Natl. Acad. Sci.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Pooja Jain, Ph.D.
Professor
Microbiology and Immunology
Office Location
Queen Lane Campus, Labs G69 & G74
Phone Number
215-991-8393
E-mail
pjain@drexelmed.edu
Amount of time you are available for direct student supervision:
At least 1 hour each day and a senior lab person will oversee student training.
Any specific skills required:
Not necessarily but previous laboratory experience will be a plus.
Project Information:
Project Name
Restoring anti-viral immunity during HTLV-associated cancer and neuroinflammatory disease
Project DescriptionRU$UHDRI,QWHUHVW
Worldwide, 20 million people are infected with HTLV-1, a majority of which remain asymptomatic carriers (ACs), while a few
develop ATL or HAM/TSP with no effective treatment or vaccine for either disease state. The exact mechanism(s) of disease
pathophysiology remain unresolved with a big question of high proviral load in HAM/TSP patients despite vigorous cellular
immune response (primarily directed towards viral transactivator protein Tax)? Our initial studies implicated programmed
death (PD)-1 receptor and its ligand, PD-L1 as potential underlying factors for observed immune cells’ dysfunctions leading to
viral persistence and disease progression, primarily in HAM/TSP patients. PD-1:PD-L1/PD-L2 are the members of
immunoglobulin superfamily (IgSF) co-signaling molecules and have been linked with CD8 T-cell exhaustion during chronic
viral infections. Several members of this family play critical role in regulating antigen-specific immune responses. Thus far,
PD-1 and CTLA-4 pathways have been extensively studied; and blocking antibodies against these have shown clinical benefit
in the setting of both cancer and chronic viral infections. More recent data suggest that blocking multiple inhibitory receptors
simultaneously may improve T-cell based therapies, but further studies are required to clarify the role of each inhibitory
receptor-ligand pair, as listed above. Moreover, the clinical applicability of checkpoint blockade remains to be tested with
respect to neuroinflammatory diseases especially those associated with chronic infection, such as HAM/TSP, NeuroAIDS, etc.
Interestingly, HTLV-1 provides a good model for both and thus, we find it significant to investigate the role of key inhibitory
receptors/ligands in HTLV-1 infection and test their combined blockade as potential immunotherapeutic strategy to restore
immune cell functions in HAM/TSP patients.
Given the latest identity of a functional lymphatic system within the CNS (Louveau et al., Nature, 2015), it has become crucial
to elucidate the role of these immune balancing pathways in the context of neuroinflammation. Therefore, this approach is both
timely and highly significant with great potential of being successful. While this approach should help in restoring functions of
pre-existing antiviral immunity in patients, activating new CTLs to mimic polyclonal CD8 T-cell response found in ACs will be
the key for a successful immunotherapeutic intervention of HTLV-associated diseases. Therefore, we propose to systematically
identify T-cell epitopes presented by HTLV-1-infected cells that define protective immunity in silent carriers alongside
blocking inhibitory pathways in order to fully restore T-cell functions in chronically infected patients. These studies will
advance the current understanding of a human chronic viral infection, and bring the field closer to finding a better treatment or
cure for HTLV-1-associated diseases.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Dr. Suresh Joshi
Assistant Professor, Director, Center for Surgical Infection & Biofilm
Microbiology and Immunology
Office Location
245 N. 15th Street Mail Stop 1013A
Phone Number
215-762-8431
E-mail
Suresh.Joshi@drexelmed.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
Definite background of microbiology lab work/research
Project Information:
Project Name
1. Studies on non-thermal plasma-activated novel antimicrobial products
2. Drug synergy approach in control of MDR Acinetobacter baumannii
Project Description or Area of Interest
Project 1:Studies on non-thermal plasma-activated novel antimicrobial products
Our laboratory is engaged in investigating the mechanisms of antibacterial and antibioflm aspects of plasma-activated products,
including studies on wound infection and healing. The student must have a strong interest in research and background in
microbiology or infection control. Cell and Molecular Biology techniques are preferred.
Project 2: Drug synergy approach in control of MDR Acinetobacter baumannii
Ongoing studies on the mechanisms underlying the resistance and the action of drug synergy compounds. Strong interest in
research; and background in microbiology, and Cell Biology or Molecular Biology techniques are required.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Sandhya Kortagere
Title
Associate Professor
Department
Microbiology & Immunology
Office Location
G81
Phone Number
215-991-8135
E-mail
sandhya.kortagere@drexelmed.edu
Amount of time you are available for direct student supervision:
70%
Any specific skills required:
Experience in handling rats
Project Information:
Project Name
In vivo screening of novel small molecules for treating Parkinson's disease
Project Description or Area of Interest
Our laboratory is interested in developing novel therapeutics for treating the motor and cognitive symptoms of Parkinson's
disease (PD). We have recently characterized small molecules that may have the property of modifying the disease in addition
to treating the symptoms. These small molecules can be neuroprotective and/or delay the onset of the motor symptoms of PD.
In this proposal we would like to assess these features of the compounds in a rodent model of PD. Results from this study will
provide further insights into the mechanism of action of these compounds in vivo.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
J. Yasha Kresh
Professor and Research Director
Cardiothoracic Surgery and Medicine (Cardiology)
Office Location
6320 NCB (Hahnemann Univ Campus)
Phone Number
215 762-1703
E-mail
jkresh@drexelmed.edu
Amount of time you are available for direct student supervision:
No restriction on time commitment (not subject to time limitation)
Any specific skills required:
Aptitude and interest in Bio-Physics, Fluid Mechanics, Bio-Engineering, Mathematical Modeling (CFD), Flow Visualization
Project Information:
Project Name
Cardiac Structure-Function: Helical Morphology, Torsional Motion, Spiral Flow
Biologically-inspired spiral laminar-flow generation: Biophysical regulation and emulation of epigenetic vascular states
Project Description or Area of Interest
Historically, much of the research conducted has been at the interface of medicine and engineering, dedicated to the discovery
and development of innovative methodologies (molecular/cellular therapies) and technologies (organ function replacement,
surgical robotics, and cellular replacement therapies) for the treatment of CV system disorders. These efforts draw upon a large
multidisciplinary knowledge base, applying the thinking, phenomena, techniques, and technology of cardiovascular biophysics,
molecular biology, cellular and tissue engineering, mathematical / computational biology and systems science theory. The basic
research encompasses integrative aspects of cardiovascular structure-function, studying the functional relationships between
intercellular and extracellular mechano-transduction signaling. The applied research targets therapies to repair / replace the
failing pump function of the heart using regenerative tissue engineering and mechanical cardiac replacement device design
technologies. More recently, we have embarked on a number of new (and highly translational) projects in the area of cardiac
valve design and enhancement of their performance dynamics, engineering functional 3D tissue models, digital kitting
(personalized designs) of cardiovascular implants (multi-leaflet valves, vascular prosthesis) and smart clothing.
Functional Architecture of the Heart: Torsional Contraction and Vortical Flow:
The heart has been viewed as a 'simple' pressure-propulsion pump, generating the needed force responsible for blood-flow
throughout the circulatory system. Most of not all treatments modalities to correct and/or replace cardiac structural
abnormalities are rooted in this oversimplified conceptualization. Not until very recently has the recognition of the torsional
(twisting and untwisting) motion of the ventricles during ejection and filling has gained a winder recognition of its clinical
relevance. Much of this occurred in the past decade with the advent and of sophisticated non-invasive dynamic 3-D (Echo,
MRI) imaging of the blood-flow velocity, exhibiting spiraling / vortical streamlines / patterns. The epigenetic significance
(molecular signaling, adaptation, pathogenesis) of this more complex, momentum imparted, spiral flow in normal physiology
and its alteration in heart failure and how it relates to vascular pathophysiologic states (atherosclerosis, thrombosis) will be
elucidated in the ongoing and future studies.
Using biomimicry by which the helical (spiral winding) structure of the contracting heart muscle band gives rise to vortical /
rotational circulatory flow are inspiring the design of vascular prosthesis (grafts / stents) and mechanical circulatory assist
devices. In particular, the (patho)physiological importance of spiral-laminar flow (endothelial shear-stress distribution,
turbulence / secondary flow formation) in the atheroma prone regions of the circulation (e.g. aortic arch, carotid-artery
bifurcation) will be the focus of the Summer Research Project.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Dong Heun Lee, MD
Assistant Professor of Medicine
Internal Medicine (Divsion of Infectious Diseases and HIV Medicine)
Office Location
245 North 15th Street, MS461, NCB 6417, Philadelphia, PA, 19102
Phone Number
215-762-4697 (Pager 41481)
E-mail
Dong.lee@drexelmed.edu
Amount of time you are available for direct student supervision:
About one to two half day per week.
Any specific skills required:
Interest and passion for clinical research. It would be great if has basic knowledge of data process and statistical analysis.
Interest in Infectious Diseases and organ transplant.
Project Information:
Project Name
Evaluation of listing process in HIV infected patients for renal transplantation
Project Description or Area of Interest
After the introduction of combination antiretroviral therapy (cART), mortality and morbidity associated with HIV disease
improved dramatically.(1) Patients with HIV diseases are no longer struggling with opportunistic infections, but rather suffering
from chronic medical conditions including malignancy and end organ diseases. (2) HIV infected patients in need of organ
transplantation experience the same frustration as uninfected patients on the wait list due to limited organ availability. Death is
not uncommon among patients who are on the wait list.
Solid organ transplantation in HIV infected patients was controversial as it may further suppress the immune system and
expose opportunistic infections. A series of solid organ transplantations was performed and it was reported to be safe and to
improve the quality of HIV patients’ lives. (3) (4) In 2003, the prospective-multicenter cohort was organized to evaluate
outcomes of liver and kidney transplantation. This study addressed HIV-specific risks of transplantation and also addressed the
information that was necessary to manage medical and psychosocial complications in this population. (5) The outcome of the
transplantation in this cohort was acceptable with no increases in complications associated with HIV infection. However, more
rejections were observed at the beginning. Both graft and patient survival rates were equivalent to those of transplants
performed on an elderly population.
On November 21, 2013, President Barack Obama signed the law the HIV Organ Policy Equity (HOPE) Act, legalizing the
use of HIV infected organs for transplantation into HIV infected patients, which is an operation rooted from experience in
South Africa. In 2010, Muller and colleagues reported their experience using HIV infected kidney donors for 4 patients. (6)
They further explored the possibility of using HIV infected donors on 10 more patients and reported all transplanted patients
had well controlled HIV infection during follow up period. They concluded use of HIV-infected donor would benefit HIV
infected patients with end stage renal diseases. (7) In a mathematical model using the database analysis, it was estimated that
500 donors might be added to the pool with the addition of HIV donors in U.S. (8) This will allow a significant increase in the
number of transplantations for HIV infected patients who are waiting for organ transplantation.
Despite the expected increase in the number of transplantations for in HIV infected patients, there is scant information about
the number of patients who are waiting for transplantation. Data is not available on HIV-status among patients awaiting organ
transplants, so it is hard to know how many patients on the wait list are HIV-positive. However, HIV infected patients who
came for renal transplantation evaluation tend to not complete the full evaluation, which allows them to be actively listed for
transplantation.(9) Among 309 potentially-eligible HIV patients only 20% completed the evaluation process to be listed
compared to 73% in HIV negative patients. The main barriers were obtaining HIV related information from providers and the
inability to complete the work up related to transplantation. The average times for listing was 16 months from the initial
evaluation, which was much longer than in HIV negative patients. This may be related to the social economic status of patients,
requiring further supports in order to complete the evaluation process.
In order to prepare for the impact of available organs from HIV infected donors in the U.S., a more-detailed understanding of
the evaluation process and the clinical characteristics of HIV infected patients who are waiting for organ transplantation is
required. This will require an in-depth analysis of potential recipients, specifically examining the evaluation process, the cause
of kidney failure, co-morbidities, vaccination status, HIV resistance, and cART that will affect future immunosuppressant use.
Understanding the patient’s socio-economic status and current support system will allow for planning a support system for post
transplantation care. Having an understanding of the HIV patients who are in the evaluation process can further speed up the
process and help prepare for the transplantation by allocating the appropriate organs. We propose to do this through a
retrospective chart review of individuals with HIV who have been evaluated and are on the wait list for kidney transplantation.
In this way, we hope to provide a greater insight into the feasibility of simplifying listing process of HIV infected recipients for
transplantation. We decided to describe the characteristics of HIV patients who came for evaluation of kidney transplantation in
order to have a better understanding and also find the gaps that may be filled to improve the process.
Objective
The purpose of this study is to determine the evaluation process of HIV infected individuals for kidney transplantation and to
describe the clinical characteristics of patients who are referred to transplant center in order to fill improve in the gaps in the
evaluation process.
1.
RH, Jr., Dworkin MS. Trends in diseases reported on U.S. death certificates that mentioned HIV infection,
1987-1999. Journal of acquired immune deficiency syndromes. 2002;29(4):378-87. PubMed PMID: 11917243.
2. Strategies for Management of Antiretroviral Therapy Study G, El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, et
al. CD4+ count-guided interruption of antiretroviral treatment. The New England journal of medicine. 2006;355(22):2283-96.
doi: 10.1056/NEJMoa062360. PubMed PMID: 17135583.
3. Stock PG, Roland ME, Carlson L, Freise CE, Roberts JP, Hirose R, et al. Kidney and liver transplantation in human
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Eishi Noguhi
Associate Professor
Biochemistry and Molecular Biology
Office Location
NCB 11319
Phone Number
215-762-4825
E-mail
enoguchi@drexelmed.edu
Amount of time you are available for direct student supervision:
Approx. 1 hr per day. However, graduate students and lab manager are often available to guide a medical student.
Any specific skills required:
Basic biochemistry and molecular biology techniques, cell culture experience, microbial culture.
Project Information:
Project Name
Role of Maf1 in lifespan regulation
Project Description or Area of Interest
We will establish the role of Maf1 as a critical target of the mTOR pathway, which plays a central role in controlling cell
growth, proliferation, metabolism, ultimately regulating cellular lifespan and senescence. This pathway has significant clinical
relevance; mTOR inhibition ameliorates multiple age-related diseases in animal models including Alzheimer's disease,
Parkinson's disease, and idiopathic senile cardiomyopathy. Thus, the identification of additional mediators of mTOR will
provide novel drug targets that may be valuable in several disease states.
We will use human cells to establish the role of Maf1 in mammalian lifespan regulation. We will downregulate Maf1 and
examine general aging-related phenotypes, including elevation of ROS, protein oxidation, and DNA damage under
calorie-restricted conditions. We may also consider investigating mitochondrial function and lipid metabolism as they relate to
lifespan regulation and insulin signaling. These experiments will establish mechanisms of Maf1 in lifespan extension.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Juan Lucas Poggio, MD, MS, FACS, FASCRS
Associate Professor of Surgery
Surgery
Office Location
245 N. 15th Street, MS 413
Phone Number
6103313720
E-mail
Juan.Poggio@DrexelMed.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
None
Project Information:
Project Name
Best teaching tools from the medical student perspective.
Project Description or Area of Interest
This survey looks at evaluating which methods are seen as most beneficial in teaching medical students during surgical
rotations. Tool to answer question will be a survey.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Juan Lucas Poggio, MD, MS, FACS, FASCRS
Associate Professor of Surgery
Surgery
Office Location
245 N. 15th Street, MS 413
Phone Number
6103313720
E-mail
Juan.Poggio@DrexelMed.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
Some knowledge on database analysis and regression analysis preferred but not required
Project Information:
Project Name
Comparison between laparoscopic and open lysis of adhesions for small bowel obstruction
Project Description or Area of Interest
Evaluate morbidity and success of both laparoscopic and open approaches to lysis of adhesions for small bowel obstruction
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Juan Lucas Poggio, MD, MS, FACS, FASCRS
Associate Professor of Surgery
Surgery
Office Location
245 N. 15th Street, MS 413
Phone Number
6103313720
E-mail
Juan.Poggio@DrexelMed.edu
Amount of time you are available for direct student supervision:
Research done with co-investigator Dr. Zulfiya Orynbayeva, PhD, Research Assistant Professor Department of Surgery,
Drexel University College of Medicine
Any specific skills required:
Teaching and education on methodology and experiments provided
Project Information:
Project Name
“Bioenergetic Signature of Colon Cancer”
Project Description or Area of Interest
Study the role of oxidative capacity and SLC13A(2,3) in bioenergetic reprogramming of colon tumor
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Juan Lucas Poggio, MD, MS, FACS, FASCRS
Associate Professor of Surgery
Surgery
Office Location
245 N. 15th Street, MS 413
Phone Number
6103313720
E-mail
Juan.Poggio@DrexelMed.edu
Amount of time you are available for direct student supervision:
Research done with co-investigator Dr. Zulfiya Orynbayeva, PhD, Research Assistant Professor Department of Surgery,
Drexel University College of Medicine
Any specific skills required:
Biostatistics knowledge preferred but not required
Project Information:
Project Name
Retraction of pathologic specimens after surgery and effects on pathologic analysis
Project Description or Area of Interest
We hypothesize that there is significant differences between intraoperative measurments of specimen and postoperative
pathologic measurements.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Juan Lucas Poggio, MD, MS, FACS, FASCRS
Associate Professor of Surgery
Surgery
Office Location
245 N. 15th Street, MS 413
Phone Number
6103313720
E-mail
Juan.Poggio@DrexelMed.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
Proactive attitude, hard work, and commitment. Statistical analysis knowledge and software use is preferable
Project Information:
Project Name
Several projects which vary from robotic surgery and database analysis to factors affecting success in medical school
Project Description or Area of Interest
Robotic Surgery Colon and Rectal Cancer and national database analysis ( access to care, outcomes according to income,
geographic location, education, insurance and ethnicity) Quality improvement research Medical education and medical schooltools to predict success
Projects are developed with me from conception to planification, application of methodology, evaluation of results and
conclusion with the goal to result in poster or oral podium presentations and peer reviewed publication
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Ramesh Raghupathi
Professor
Neurobiology and Anatomy
Office Location
Room 277, Queen Lane campus
Phone Number
215-991-8405
E-mail
ramesh.raghupathi@drexelmed.edu
Amount of time you are available for direct student supervision:
2-3 hours/day
Any specific skills required:
Interest in brain injury
Project Information:
Project Name
Interventions to ameliorate long term behavioral deficits following repetitive concussions
Project DescriptionRU$UHDRI,QWHUHVW
Both student and professional athletes are at risk of suffering from the long-term consequences of multiple concussions. This
has been highlighted and documented in retired NFL players whose brains show signs of chronic degeneration. Student athletes
complain of cognitive problems, emotional disability and psychiatric symptoms during their high-school and college careers.
Importantly, men and women suffer distinct sets of behavioral problems. We have established a clinically-relevant rodent
model of repetitive mild concussions wherein we have demonstrated deficits in cognition, increased impulsive behavior, and
decreased sensitivity to pain that is evident for 1-2 months after the injury. We have two approaches designed to reduce these
behavioral problems: (1) a pharmacological approach using agents that target the dopamine system (eg amantidine), and (2)
physical activity (eg forced exercise using a treadmill). The current project is designed to compare the efficiency of these two
interventions in both male and female rodents with the idea that the efficacy of the intervention may depend on the sex and/or
the behavioral outcome being measured.
The project will entail that the student will learn aspects of brain injury (concepts), behavior (methods and data analysis), and
pharmacology (drug dosing and delivery).
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Scott D. Richard
Chief of Gynecologic Oncology
OB/GYN
Office Location
230 N Broad St., Rm 1536 South Tower
Phone Number
215-762-2640
E-mail
Scott.Richard@drexelmed.edu
Amount of time you are available for direct student supervision:
20 hours per week
Any specific skills required:
Previous experience with cell cultures or with rodents preferred but not required.
Project Information:
Project Name
Treatment of Peritoneal Dissemination of Multi-Drug Resistant Ovarian Cancer with Synthetic Cell-Cycle Derived Peptide.
Project Description or Area of Interest
There are 25,000 newly diagnosed women with ovarian cancer every year in the United States, at a median age of 63.
Particularly problematic is that most of these women (61%) are diagnosed at a late stage, as the anatomy makes peritoneal
“seeding” more likely. 5-year survival remains below 50% overall, and around 25% for those with metastases. Peritoneal
dissemination of ovarian cancer portends a grim prognosis, hence the need for innovative therapies. We have been investigating
novel synthetic peptides modeled on a key domain of the p53 gene product, PNC-27 and PNC-28. Originally designed to hijack
the apoptosis apparatus and induce tumor cell death, subsequent studies have shown a different, membranolytic mechanism of
action; sparing of untransformed cells remains a hallmark feature. Multidrug resistant ovarian cancer offers the perfect
paradigm for preclinical testing of peptide efficacy and safety.
Medical student fellows will work directly with both MDs and PhDs in a collaborative multidisciplinary basic
science/translational laboratory with a strong track record of working with students. Opportunities will be provided for
additional projects including clinical outcomes and health services research. This project is perfect for those interested in
gynecologic oncology, obstetrics and gynecology, surgical oncology, general surgery, medical hematology-oncology, radiation
oncology, women’s health, geriatrics, palliative care, internal medicine, drug development, rational drug design, public health,
medical innovation, or anyone interested in the nexus of basic science research and clinical therapeutics.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Christian Sell
Associate Professor
Department
Pathology
Office Location
NCB 5219
Phone Number
215-762-8367
E-mail
christian.sell@drexelmed.edu
Amount of time you are available for direct student supervision:
7 days a week
Any specific skills required:
some basic bench skills would be a plus.
Project Information:
Project Name
Influence of mitochondrial variation on neurocognitive status and longevity.
Project Description or Area of Interest
Mitochondria are the central energy producing organelles in mammalian cells. Mitochondria produce 92% of cellular ATP,
critical metabolic intermediates, and play critical roles in calcium regulation, thermogenesis, and apoptosis. Within the cell,
mitochondria exist as a highly dynamic network that is actively remodeled through fission and fusion events. The mitochondrial
genome is found within the matrix of the mitochondria and, unlike the multi-chromosome configuration of nuclear DNA, which
contains both introns and exons, the mitochondrial genome is intronless, circular and approximately 16,569 base pairs in size
for humans. Depending on cell type, circular mitochondrial DNA copies can range from 1000 to 8000 per cell. Mitochondrial
haplogroups have been found to be associated with an increased risk of several neurodegenerative disorders and potentially
with differences in longevity, and an increase in the number of deletions and mutations within the mitochondrial genome occurs
with age. HIV-1-infected patients are prone to premature aging and dementias, such as Alzheimer's disease and HIV-associated
neurocognitive disorder (HAND). HAND is thought to be caused by a combination of viral infection and side effects from
antiretroviral therapy. Antiretroviral therapies are known to damage mitochondria and this damage is thought to contribute to
HAND and premature aging. Given that the HIV-1-infected population is now aging (26% of HIV-1-infected individuals were
>50 in 2011 and this percentage is increasing) the identification of patients at risk for mitochondrial dysfunction and
neurocognitive decline is critical for clinical management and will become increasingly important as this patient population
continues to age. In a collaborative effort involving infectious disease specialists, clinical neuropsychologists, and basic
scientists; we have examined genetic variation within the mitochondria genome in a population of primarily African American
HIV-1-infected patients that have undergone extensive cognitive evaluation and found that a subset of these variants correlate
with specific aspects of neurocognitive function and status. Some variants appear to be protective while others convey a greater
risk for neurocognitive decline. We predict that the variants that are neuroprotective will also enhance longevity. We propose to
move this study forward by first enrolling additional patients for neurocognitive assessment and genomic sequencing to
increase the statistical power of the study and second, examining the mitochondrial genome of healthy centenarians for genetic
variation associated with enhanced longevity. The successful candidate will be involved in patient recruitment, sample
processing, and some data analysis. Both clinical skills and basic research skills would be involved and the student will act as a
go between for the laboratory and clinical sites.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Todd Strochlic V.M.D., Ph.D.
Assistant Professor
Department
Biochemistry and Molecular Biology
Office Location
New College Building - Room 11315
Phone Number
215-762-3664
E-mail
Todd.Strochlic@drexelmed.edu
Amount of time you are available for direct student supervision:
May 15, 2016 - August 15, 2016
Any specific skills required:
Some experience with basic techniques in molecular and cell biology preferred
Project Information:
Project Name
Investigating the role of MK2 kinase signaling in inflammatory breast cancer
Project Description or Area of Interest
Inflammatory breast cancer (IBC) is a relatively rare but highly aggressive form of locally invasive breast cancer accounting for
approximately 5% of all breast cancer cases. Because the disease initially resembles mastitis and there is usually no palpable
mass, patients are frequently diagnosed late in the progression of the disease with advanced metastatic spread. As a result, IBC
carries a guarded to poor prognosis and has a 5-year disease-free survival rate of only 40%, the lowest of all breast cancer
types. Given the poor survival rate and aggressive nature of this form of breast cancer, surprisingly little is known regarding its
genetic and biochemical basis, underscoring the need for further investigation into the molecular etiology of IBC in order to
improve patient outcome. As critical regulators of cell signaling pathways, protein kinases play key roles is mediating cell
growth, proliferation, and motility and are frequently mutated in human cancers. We have obtained preliminary data indicating
that the stress-activated protein kinase MK2 (MAPKAP kinase 2) is hyperactive in IBC compared to non-IBC cells. We have
found that shRNA-mediated knockdown of MK2 decreases the secretion of IL-6 and IL-8, pro-inflammatory cytokines critical
for the proliferation of IBC cells, indicating that MK2 is involved in this process. To further characterize a role for MK2 kinase
signaling in IBC, we conducted a proteomic screen to identify novel substrates of this kinase in the SUM149 IBC cell line.
Using this approach, we have identified and validated a novel MK2 substrate, the DNA helicase RecQL, an enzyme implicated
in the maintenance of genomic integrity. Our overall hypothesis is that MK2 drives the progression of IBC by both promoting
the secretion of pro-inflammatory cytokines and by regulating the activity of RecQL. Experiments to test these hypotheses will
utilize techniques including molecular cloning, site-directed mutagenesis, protein expression and purification, Western blotting,
and cell proliferation and motility assays.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Zsofia Szep
Assistant Professor of Medicine
Department of Medicine Division of Infectious Diseases and HIV Medicine
Office Location
1427 Vine St 412
Phone Number
267-507-6738
E-mail
zsofia.szep@drexelmed.edu
Amount of time you are available for direct student supervision:
20 hours per week
Any specific skills required:
Assist with data collection and data entry during the summer of 2016
Project Information:
Project Name
Incorporating Screening for Pre-exposure Prophylaxis into Rapid HIV Testing in a High Risk Neighborhood in Philadelphia
Project Description or Area of Interest
Pre-exposure prophylaxis (PrEP) is a bio-medical HIV prevention strategy that involves the use of antiretroviral medications to
reduce HIV acquisition among at-risk individuals. PrEP trials have shown efficacy among MSM, heterosexual men and women
and intravenous drug users (IDUs). Although the U.S. Food and Drug Administration approved PrEP in 2012, adoption of PrEP
in real-world clinical settings has been slow. Reasons for slow adoption include lack of access to providers willing to prescribe
PrEP, cost and low PrEP knowledge among high-risk populations. Despite slow adoption overall, implementation studies in
France and in England in the MSM population have shown highly successful results with 86% reduction in HIV acquisition. A
recent study from San Francisco documented no new cases of HIV infections among 650 MSM using PrEP despite high-risk
sexual behaviors.
Given its potential to curb HIV transmission, scale up of PrEP, that includes targeted efforts for at-risk populations is
warranted. The uptake of PrEP could, however, be increased if individuals in high-risk settings were screened for, educated
about PrEP during rapid HIV testing and then referred to a clinic where practitioners feel comfortable providing PrEP care
(prescribing PrEP and quarterly follow-up). Through this application, we will incorporate PrEP screening into HIV rapid testing
in Kensington a low income neighborhood with concentrated HIV/STD and a large Latino population. To the best of our
knowledge, there have been no studies of PrEP implementation studies targeting a high-risk Latino community. We propose the
following specific aims and select hypotheses:
Aim #1: To pilot a screening tool for PrEP screening during rapid HIV testing and link those who qualify into PrEP Care
H1: Incorporating PrEP screening into HIV testing will identify individuals who qualify for PrEP.
H2: Rates of PrEP eligibility in Kensington will meet or exceed those in implementation studies.
Aim #2:To identify factors associated with failure to link to PrEP Care among individuals who qualify for PrEP
H3: Predisposing factors, enabling factors, and perceived need will be associated with non-linkage to PrEP care.
Aim #3: To evaluate rapid HIV testers’ knowledge and attitudes about PrEP prior to and after incorporating screening for PrEP
into rapid HIV testing.
H4: Tester knowledge and attitudes toward PrEP will improve from baseline to follow-up and this will be associated with
higher comfort providing referrals to PrEP care.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Claudio Torres
Associate Professor
Pathology
Office Location
NCB, 5610
Phone Number
215-762-1783
E-mail
claudio.torres@drexelmed.edu
Amount of time you are available for direct student supervision:
As required
Any specific skills required:
Although not absolutely necessary, knowledge of some basic laboratory techniques such as use of pipettes and preparation of
solutions is desirable
Project Information:
Project Name
Role of Cellular Senescence on Neurodegenerative Disease
Project DescriptionRU$UHDRI,QWHUHVW
Aging is the greatest risk factor for the development of neurodegenerative disease, however the aspects of the aging process
that predispose to the development of brain pathology are largely unknown. A recent advance in the basic biology of aging, that
may have implications for brain disorders, is the recognition by our laboratory that senescent astrocytes and neurons can be
identified in vivo. Astrocytes are the most abundant cell type in the brain with critical roles in brain physiology and neuronal
function. However, little is known about the changes that occur in these cells during aging and neurodegenerative disease.
Recently, we have reported that human astrocytes activate a senescence program in response to oxidative stress or exhaustive
replication. Astrocytes are very sensitive to oxidative stress and we hypothesized that astrocyte senescence may occur in
neurodegenerative disorders or inflammatory episodes, such as Alzheimer’s disease (AD). Brain tissue from AD patients
contains a significantly higher number of astrocytes and neurons expressing markers of senescence than age-matched controls.
The demonstration that senescent cells accumulate in aged and AD brains, and that these cells lose functionality, creates a new
paradigm for aging-related pathologies and AD. These studies will finally enhance our understanding of why age is the major
risk factor for AD independent of gene mutations, and will lead the way to interventions aimed to delay cellular senescence or
reduce the effects of senescent cells in AD progression.
The project to be developed during the time frame of a summer rotation could be included as part of some of our current
research projects shown below. Specific goals for the summer project will be defined in conjunction with the student.
1. Verify the extent of astrocyte and neuron senescence in brains affected by AD and frontotemporal lobar degeneration
(FTLD) by analyzing functional markers of senescence including chromatin condensation and telomere dysfunction, and
epigenetics changes in histones.
2. Evaluate the relationship between oxidative stress on astrocyte and neuron senescence.
3. Evaluate the ability of senescent astrocytes to influence microglial activation and neuronal senescence. We hypothesize that
specific factors secreted by senescent astrocytes, such as cytokines and miRNAs, influence neuronal and microglial
homeostasis to contribute to the pathogenesis of AD. We are studying effects on neuron survival, microglial activation and the
identification of secreted factors involved in the process.
4. Evaluate relation HIV-1 and cellular senescence. We hypothesize that HIV-1 infection induces the senescent program in the
brain cells. We will perform an evaluation of astrocyte and neuron senescence in the brain after HIV infection. In addition, we
are evaluating the role of viral factors, antiviral drugs and drugs of abuse such cocaine and morphine on the cellular senescence
program in vitro.
2016 Medical Student Summer Research Fellowship
Project List
Faculty Sponsor
Title
Department
Eileen K. Jaffe
Adjunct Biochemistry Faculty at Fox Chase Cancer Center
Biochemistry and Molecular Biology
Office Location
Fox Chase Cancer Center
Phone Number
215 728-3695
E-mail
Eileen.Jaffe@fccc.edu
Amount of time you are available for direct student supervision:
Any specific skills required:
Project Information:
Project Name
Optimizing crystallization conditions for determining the structure of phenylalanine-stabilized fully-activated phenylalanine
hydroxylase
Project Description or Area of Interest
Dysfunction of the enzyme phenylalanine hydroxylase (PAH) is the root cause of most forms of phenylketonuria (PKU) and/or
hyperphenylalaninemia (1, 2). PAH functions to maintain phenylalanine (Phe) at levels sufficient for the body’s need for
protein biosynthesis but below neurotoxic levels. This delicate control is accomplished by Phe acting as an activator of PAH in
response to a protein-containing meal. Despite the success of a protein-restrictive diet in preventing permanent neurological
damage in infants and children with PKU, there is a clear need for additional therapeutic measures to counteract the behavioral
and psychiatric problems associated with adolescents and adults who struggle with the necessary dietary restrictions (1). New
therapeutics can arise from a thorough understanding PAH structure.
In 2013 we described a novel structural paradigm for PAH activation by Phe, which consists of two different tetrameric PAH
conformations (3). One conformation represents an auto-inhibited enzyme form with basal activity, which is functional when
Phe levels are low. We have recently solved the X-ray crystal structure of this auto-inhibited tetrameric form (4), which
represents a major contribution to the field. The second tetramer represents the activated form of the enzyme, which is
stabilized by allosteric Phe binding when Phe levels are elevated. The goal of the proposed DUCOM medical student summer
fellowship project is to optimize crystallization conditions that will allow determination of the structure of the Phe-stabilized
activated PAH tetramer. Determining this structure will provide a long-needed target for structure-based design/discovery of
small-molecule therapeutics that can stabilize activated PAH to serve patients throughout life.
Our 2013 proposal for PAH regulation predicted that the activated PAH structure would relieve an autoinhibitory interaction
seen in our current crystal structure and would contain a new inter-subunit protein-protein interface that defines the location of
allosteric Phe binding. This new interface is a target for developing a drug that will stabilize activated PAH. Transformation
from the autoinhibited to the activated form is predicted to include significant repositioning of structural domains within each
subunit.
The medical student summer fellow would work closely with graduate student Emily Arturo to optimize crystallization
conditions in the presence of Phe. The laboratory already has copious amounts of purified full length mammalian PAH. The
search for suitable crystallization conditions is being carried out initially on a Mosquito robotic instrument using a variety of
commercial screening kits. Conditions will be optimized by making small systematic changes in the crystallization solutions.
In the event that promising crystals are obtained, the medical student may participate in screening these crystals for diffraction
quality. The medical student may also participate in harvesting the crystals to be mailed to Argonne National Laboratory for
remote data collection.
Alternative approaches – If necessary, alternative forms of PAH can be used to derive a crystal structure for the Phe-stabilized,
high-activity PAH tetramer. These forms include 1) an N-terminal truncation lacking the autoinhibitory peptide, 2) full-length
PAH that is phosphorylated at Ser16, or 3) a phosphomimic PAH variant S16E. It is possible that the medical student may
participate in the purification of these alternate forms of PAH.
References
1. Camp KM, et al. (2014) Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol
Genet Metab 112(2):87-122.
2. Blau N, Shen N, & Carducci C (2014) Molecular genetics and diagnosis of phenylketonuria: state of the art. Expert review of
molecular diagnostics 14(6):655-671.
3. Jaffe EK, Stith L, Lawrence SH, Andrake M, & Dunbrack RL, Jr. (2013) A new model for allosteric regulation of
phenylalanine hydroxylase: implications for disease and therapeutics. Arch Biochem Biophys 530(2):73-82.
4. Arturo E, et al. (2016) The First Structure of Full-Length Mammalian Phenylalanine Hydroxylase Reveals the Architecture
of an Auto-inhibited Tetramer. Revised manuscript under review by Proc. Natl. Acad. Sci.