Faculty
Program Director
Member: FRANK W. LOGERFO, M.D.
Position: William V. McDermott Professor of Surgery at Harvard Medical School
(HMS); Chairman, Department of Surgery; Chief, Division of Vascular Surgery at
the Beth Israel Deaconess Medical Center (BIDMC)
Research Area: Projects in this laboratory focus on the mechanisms of prosthetic arterial
graft failure and the development of methodology to improve prosthetic graft patency. A longstanding project is the investigation of the genetic events occurring at the anastomosis between
an arterial graft and the host artery. This is a particularly problematic site of development of
intimal hyperplasia leading to graft failure. In these studies, RNA display has been used to
determine differences in gene expression between the anastomosis and the normal host artery.
One of our trainees successfully isolated a gene fragment and identified a gene that is strongly
expressed in a normal artery but, normally, is minimally expressed in the hyperplastic areas.
Subsequently another trainee was able to pull the entire gene, now referred to as interferon
gamma unregulated protein gene (IGUP), to clone it, obtain the protein, and is now working to
identify the role of the protein in arterial wall biology.
A second major area of investigation is in the development of biologically active surfaces to
prevent thrombosis on vascular grafts and to stimulate full cellular incorporation of the gene graft
into the host tissues. A trainee successfully applied technology for covalent linkage of proteins to
the Dacron graft surface. In addition, he successfully demonstrated that immobilized VEGF will
remain functional and stimulate growth of endothelial cells on the surface. Future trainees will
continue to work on these related projects. Access to scientists with expertise in all aspects of
molecular biology, biochemistry and textile engineering is immediately available.
Core Faculty
Member: BRUCE R. BISTRIAN, M.D., PH.D.
Position: Professor of Medicine at HMS; Chief, Clinical Nutrition & Director of
Nutrition/Infection Laboratory at BIDMC
Research Area: Efforts in the Laboratory of Nutrition and Infection have been directed at
investigating the metabolic and clinical aspects of novel fats such as structured lipids and
physical mixtures of fish oil and medium chain triglycerides in animal models and humans. A
second focus is on the physiologic aspects of cytokine metabolism, as well as their impact on
signal transduction on anabolic pathways. The Laboratory of Nutrition and Infection has been
carrying out NIH-supported research in these fields for the past 13 years.
Member: LEWIS C. CANTLEY, PH.D.
Position: Professor of Cell Biology at HMS; Chief, Division of Signal
Transduction at BIDMC
Research Area: Dr. Cantley’s investigations seek to understand the signal transduction
pathways that control cell survival, cell growth and cell transformation. Dr. Cantley’s group has
taken a molecular approach to understanding how growth and transformation-related signal
transduction pathways function. The results indicate that the primary sequence of proteins alone
can be used to make predictions about how they fit into signaling pathways. The hypotheses can
be quickly tested by expressing proteins with mutations in the predicted sequence motifs.
Ultimately, drugs can then be useful for immune suppression, and as agents to prevent
proliferative disorders, such as restenosis and various cancers. Dr. Conte has mentored two
trainees over the last four years.
Member: MICHAEL S. CONTE, M.D.
Position: Assistant Professor of Surgery at HMS; Attending Surgeon at
Brigham & Women’s Hospital
Research Area: Dr. Conte’s research efforts focus on the development of local biologic
approaches to modify the healing response of the blood vessel wall. In particular, his
investigations have sought to examine the interplay between endothelial regeneration and lesion
formation following arterial injury. Manipulation of the process by which a functional endothelial
monolayer is restored may provide a novel therapeutic target to prevent recurrent failure of
vascular interventions. Their investigations thus far suggests an important role for the
reconstituted endothelium in control of the remodeling process after arterial injury. Concurrently,
Dr. Conte’s group has a strong interest in developing improved techniques for site-specific gene
transfer to the cardiovascular system. The long-term goals of these efforts are to develop
clinically relevant applications of gene therapy to improve the long-term patency of vascular
reconstructions.
Member: PATRICIA D’AMORE, PH.D.
Position: Associate Professor of Pathology at Harvard Medical; Massachusetts
General Hospital
Research Area: Dr. D’Amore’s laboratory focuses on understanding the mechanisms that
regulate vascular growth and differentiation. The vasculature consists of endothelial cells and
vascular wall cells. In the brain and retina, a third cell type, the astrocyte, contacts vascular cells.
To elucidate the cell-cell interactions involved in vessel formation Dr. D’Amore’s group has
developed a number of coculture models. Current studies in this project include elucidation of the
role of TGF-B in SMC differentiation and investigation of mechanisms regulating smooth muscle
cell differentiation using SMC-specific promoter/reporter constructs. Vascular endothelial cell
growth factor (VEGF) has been shown to be critical for new vessel growth, both during normal
development and in various pathologic states. VEGF exists as at least alternatively spliced
proteins, but the specific roles of each VEGF isoform is not known. To approach this question,
the group has cloned the mouse VEGF gene and is generating mice that express limited VEGF
isoforms. They are also interested in understanding the regulation of VEGF. Finally, Dr.
D’Amore’s group is interested in understanding the control of endothelial differentiation.
Member: JENNIFER DOYLE, M.A.
Position: Lecturer of Surgery at HMS; Director of Educational Development and
Evaluation at BIDMC
Role: Director of the mandatory Scientific Methods & Integrity course. Ms. Doyle is responsible
for the development and direction of the program with a focus on evaluation of the program’s
progress and achievement.
Member: VICTOR DZAU, M.D.
Position: Hersey Professor of Theory and Practice of Medicine at HMS;
Chairman, Department of Medicine at Brigham & Women’s Hospital
Research Area: Dr. Dzau’s laboratory work focuses on understanding the molecular biology
of cardiovascular physiology and pathopysiology, so that new avenues of potential molecular and
genetic therapies for cardiovascular diseases can be explored. Dr. Dzau has a particular interest
in the concept of translational research, i.e., bridging the gap between rapid advances in the
realm of basic molecular science and the application of those new insights toward the
development of novel therapeutic strategies. He is especially interested in the field of
cardiovascular gene therapy not only as the treatment of inherited genetic disorders but as the
manipulation of gene expression in any somatic cell aimed at the retardation or reversal of
pathobiological processes. Given this broad definition, their goal is to identify the molecular and
genetic elements that play critical roles in target disease, and to devise a practical approach
toward the blockade or enhancement of that gene expression. Specifically, Dr. Dzau’s group has
looked at cardiovascular proliferative diseases such as restenosis and vein graft atherosclerosis,
and have developed successful gene therapy strategies based on blockage of genes essential for
the final common pathway of cellular proliferation, the cell cycle regulatory genes.
Member: CHRISTIANE FERRAN, M.D., PH.D.
Position: Assistant Professor at HMS; Associate Scientist at the Sandoz Center
for Immuniobiology at Children’s Hospital
Research Area: Dr. Ferran’s research focuses on the protective role of anti-apoptic gene in
endothelial cells. An extension has been made to the understanding of their role in smooth
muscle cells, mainly upon smooth muscle cell proliferation and prevention of atherosclerosis.
Their focus is on growth control in the vasculature and modulation of endothelial cell activation by
the anti-apoptic gene A20. Dr. Ferran has mentored one trainee over the last two years.
Member: MICHAEL GIMBRONE, JR., M.D.
Position: Elsie T. Friedman Professor of Pathology at HMS; Director, Vascular
Research Division at Brigham & Women’s Hospital
Research Area: Dr. Gimbrone heads the Vascular Research Division of the Department of
Pathology at Brigham and Women’s Hospital. The division consists of several independent
investigators, each of whom leads a research program concerned with vascular cell biology and
pathobiology, as it relates to the pathogenesis of disease, such as artherosclerosis, thrombosis,
and inflammation. The principle research areas currently under investigation include: Vascular
endothelium, (interacting with blood components, smooth-muscle cells, and extracellular matrix),
plays a central role in the pathogenesis of inflammation, immunologic reactions, thrombosis,
vascular injury and repair, and atherosclerosis. A major focus of study has been the localized
interaction of leukocytes with the endothelial lining as a key even in acute and chronic
inflammation, ischemic tissue injury, intravascular thrombosis, and the pathogenesis of
atherosclerosis. A second major emphasis (which has evolved from a long-standing
collaboration with Prof. C.F. Dewey’s fluid mechanics laboratory at Massachusetts Institute of
New
Technology) is the study of hemodynamic forces, such as wall shear stress, as modulators of
vascular endothelial structure and function. These studies have led to the discovery of sheer-
Methods
stress-response element in the promoter of certain endothelial genes that is necessary for their
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transcriptional regulation by biomechanical forces. The molecular mechanisms that link these
New
Answers
externally applied forces to genetic regulatory events in the nucleus are being dissected. Recent
studies, utilizing differential display technology, also have led to the identification of novel
endothelial genes induced by biomechanical forces. These studies may prove relevant to
physiologic vascular adaptations to altered hemodynamics as well as to the fundamental problem
of the branchpoint localization of early lesions of atherosclerosis.
Member: VICTOR GUREWICH, M.D.
Position: Professor of Medicine (Biochemistry) at HMS; Director, Vascular
Research Laboratory at Harvard Institutes of Medicine; Co-Director, Institute for
Prevention of Cardiovascular Disease at BIDMC
Research Area: In Dr. Gurewich’s laboratory, trainees have the opportunity to work on
projects relating to the detailed mechanisms involved in fibrinolysis, a key area directly related to
the increasingly important role of fibrinolytic agents in clinical surgery. The particular projects
currently under investigation are the following: 1) The structural determinants of the unusual
catalytic domain of single chain pro-urokinase. 2) The development of a site-directed mutant
form of pro-urokinase which is more stable in blood an therefore, more fibrin specific in
fibrinolysis. 3) Determination of the role of Lp(a) in fibrinolysis. It was determined that this was
related in large part to irreversible binding to fibrin rather than exclusively to a competition with
plasminogen for binding sites of fibrin. 4) The role of platelets in fibrinolysis. These studies have
resulted in the identification of a new binding protein in the platelet membrane, which binds
urokinase-type plasminogen activator irreversibly. This platelet-dependent pathway of fibrinolysis
is believed to be important to both the (pro)urokinase mediated pathway and that which is
mediated by factor XII.
Member: GEORGE L. KING, M.D.
Position: Professor of Medicine at HMS; Senior Investigator at Joslin Diabetes
Center
Research Area: Dr. King and his team study the molecular mechanisms by which
hyperglycemia may lead to vascular dysfunction and long-term diabetic complications. The group
at Dr. King’s laboratory has identified highly selective protein kinase C inhibitor that can be given
orally to inhibit PKC activity. Data from these researchers, published in Science suggest that a
PKC inhibitor can correct blood vessel abnormalities in the retina, as well as in the kidney of
diabetic animals. These studies, completed in conjunction with researchers from Eli Lilly and
Company, are now entering human trials. Dr. King’s studies on how insulin and other hormones
regulate the contraction and dialation of blood vessels are important to understanding insulin
resistance and vascular complications in people with diabetes, since insulin resistance at one
level of the blood vessel could cause either dialation or constriction, depending on the tissue
involved. Dr. King’s recent work appears to suggest that insulin can regulate the expression of
the gene that causes the hormone endothelin to be produced in the vascular endothelial cells. It
is also possible that endothelin can alter insulin action in blood vessels. The researchers’ data
clearly show that insulin and endothelin can affect each other’s actions. Besides basic studies on
the molecular biology level, Dr. Kings’ group is interested in knowing how these interactions affect
the functioning of vascular cells.
Member: ROBERT S. LANGER, D.SC.
Position: Germeshausen Professor of Chemical and Biomedical Engineering at
the Massachusetts Institute of Technology; Research Associate at Children’s
Hospital
Research Area: Dr. Langer’s laboratory focuses on the interface of biotechnology and
materials science. A major focus is the study and development of polymers to deliver drugs,
particularly genetically engineered proteins, continuously at controlled rates for prolonged periods
of time. Work is in progress in several areas, including: 1) Investigating the mechanism of
release from polymeric delivery systems with concomitant microstructural analysis and
mathematical modeling. 2) Developing controlled release systems that can be magnetically,
ultrasonically, or enzymatically triggered to increase release rates. 3) Synthesizing new
biodegradable polymeric delivery systems, which are ultimately absorbed into the body. Dr.
Langer’s lab has used these approaches to deliver drugs directly to blood vessels leading to
potential new ways of preventing restenogy. Dr. Langer and his colleagues have also
synthesized new biodegradable polymer systems to be used in mammalian cell transplants for
engineering new organs (e.g., blood vessels, heart valves). Finally, they are developing drugs
that specifically inhibit the process of neovascularization but do not interfere with existing blood
vessels.
Member: SIDNEY LEVITSKY, M.D.
Position:
David W. & David Cheever Professor of Surgery at HMS; Senior Vice Chairman
of Surgery at BIDMC
Research Area: Dr. Levitsky’s laboratory systematically studies the biology of surgicallyinduced ischemia in the senescent myocardium as compared to the mature heart. This group
hypothesizes that the mechanisms leading to decreased functional recovery following ischemia in
the aged heart is the result of progressive accumulation of genetic damage (not necessarily
mutation or deletion) which exceeds the capacity of cellular mechanisms for repair, renewal and
removal of damaged genomic molecules. Using metabolic and molecular probes in ischemic,
sexually mature and senescent rabbit hearts, the group plans to study the effects of increased
cytosolic calcium on changes in high energy phosphate moieties, mitochondrial genomic function,
nuclear homeostasis and to isolate and identify RNA transcripts (nuclear and/or mitochondrial)
associated with enhanced functional recovery to allow for the development of new myocardial
protective strategies. As a consequence of these studies, the group hopes to contribute new
information regarding the response of the aged heart to surgical ischemia and, as a corollary,
reduce mortality related to cardiac surgery in the elderly.
Member: PETER LIBBY, M.D.
Position:
Mallinckrodt Professor of Medicine at HMS; Brigham & Women’s Hospital
Research Area: Dr. Libby’s research interest is vascular biology with special reference to
atherogenesis. His group studies normal and abnormal function of smooth muscle and
endothelial cells using the tools of biochemistry and cell and molecular biology. Two major
themes of investigation include the control of smooth muscle cell proliferation and the immune
and inflammatory functions of blood vessel wall cells. Specific projects currently underway
include basic investigation of the regulation of gene expression in vascular endothelial and
smooth muscle cells, an study of the cellular mechanisms of artherogenesis as well as coronary
restenosis and transplant-associated arteriosclerosis.
Member: BING LIM, M.D.
Position: Associate Professor of Medicine at HMS; Associate Physician at
Brigham & Women’s Hospital
Research Area: Embryonal Stem Cell as a model for tissue differentiation. Applying
methods similar to colony assays for bone marrow progenitors, we and others have developed
culture conditions that allow murine totipotent embryonal stem (ES) cells to differentiate in vitro
into colonies containing myeloid hematopoietic lineages. Over the past few years, the assay has
been increasingly used and the method is now an important technique used in studies of genes
relevant to hematopoiesis, particularly in the context of genes whose loss-of-function cause
embryonic lethality. Dr. Lim’s laboratory currently two groups of projects: A) Developing
conditions that will allow differentiation of ES cells into cells of other tissues, especially
endothelial cells, neurons, cardiac muscle, osteoblasts and hepatocytes. B) Using a combination
of subtractive hybridization and differential screening, we have isolated and cloned over cDNAs
which are either specifically expressed or preferentially expressed at high levels in hematopoietic
cells. Most of the turned out to be novels genes and three of these genes are not the main focus
of my laboratory. We are applying ES cell assay to study novel genes of unknown function.
Member: KATHLEEN G. MORGAN, PH.D.
Position: Associate Professor of Physiology at HMS; Director and Amelia
Peabody Senior Scientist at the Boston Biomedical Research Institute
Research Area: Dr. Morgan’s focus in the smooth muscle cell, which forms the walls of most
of the hollow organs of the body. Inappropriate contraction or relaxation of this cell type is
responsible for a number of pathophysiological situations under collaborative investigation,
including coronary and post-hemorrhagic cerebral vascospasm and pre-term labor. The precise
mechanism of contraction of the smooth muscle cell is, to a large extent, currently unknown. The
signal transduction pathways leading to contraction and relaxation of the differentiated smooth
muscle cell are currently being investigated by the combined use of biochemical molecular, and
cellular techniques. Three areas of current research focus are: 1) the identification of the specific
kinases and regulatory proteins involved in a signal transduction pathway leading to differentiated
smooth muscle cells. 2) The mechanism by which the subcellular trafficking if kinases within the
smooth muscle cell is regulated. 3) The mechanism by which these same kinases and regulatory
proteins may also initiate growth of smooth muscle cell in physiological and pathophysiological
states under conditions of hypertrophy and hyperplasia.
Member: ROBERT C. MULLIGAN, PH.D.
Position:
Mallinckrodt Professor of Genetics at HMS; Associate Director of the Harvard
Institute of Human Genetics; Investigator, Howard Hughes Medical Institute
Research Area: Dr. Mulligan is interested in the development of methods for introducing
genes into mammalian cells and the applications of those methods in a number of areas of
biology and medicine including neurology. The current research activities of his laboratory are
focused in four general areas: 1) Hematopoiesis. 2) Modulation of immune response. 3)
cardiovascular biology, and 4) mammalian vector development. In each of these areas, the lab
has tried to organize activities so as to combine the study of specific issues of intrinsic biological
interest with practical efforts to solve some of the biological and technical issues relevant to the
use of gene transfer in different therapeutic settings (e.g., gene therapies).
Member: WILLIAM C. QUIST, M.D., PH.D.
Position: Assistant Professor at HMS; Staff Pathologist at BIDMC
Research Area: Dr. Quist directs the Vascular Research Laboratory. Major areas of interest
include mechanism of prosthetic arterial graft failure, novel prosthetic arterial grafts and
modification of biomaterial surfaces. Current trainees under Dr. Quist’s direction are using microarray investing gene regulation following prosthetic arterial grafting. Dr. Quist’s expertise include
models of vascular grafting, in situ hybridization, immunohisto chemistry and cell culture
technique. His laboratory has mentored seven trainees over the last five years.
Member: FREDERICK J. SCHOEN, M.D., PH.D.
Position: Professor of Pathology at HMS; Interim Chairman of Pathology at
Brigham & Women’s Hospital
Research Area: Dr. Schoen studies the mechanisms of failure (and subclinical interactions)
of mechanical and bioprosthetic heart valves, vascular grafts and cardiac assist devices. The
objectives of these studies are to understand the problems of currently available devices and to
develop improved designs and management studies. Three different approaches are used: 1)
Cohorts of novel types of heart valve prostheses, retrieved at reoperation or post-mortem
examination, are analyzed to establish failure modes and details of patient/prosthesis
interactions. 2) In preclinical studies, new valve configurations are implanted in sheep or valves
as actual valve replacements; the valves are studied in situ by hemodynamic monitoring and by
pathological analyses following removal, in order to predict the long-term efficacy and safety of
these designs, to predict complications, and to develop new materials and configurations. 3) In
basic studies, the mechanisms of calcification, the major cause of failure of contemporary
bioprosthetic valves, are investigated using subcutaneous implants of these tissues in rats and
mitral valve replacements in sheep, followed by detailed pathological and biochemical analysis.
These investigations have delineated clinicopathologic correlates and host and implant
determinants of failure, as well as critical early events in the pathogenesis of calcification, on
which potentially useful therapies are based and being evaluated.
Member: MICHAEL SIMONS, M.D.
Position:
Associate Professor of Medicine at HMS; Director, Cardiovascular Angiogenesis
Center at BIDMC
Research Area:
Angiogenesis is a complex process involved in a number of physiologic and pathophysiologic
processes. However, little is understood about the processes involved in its regulation. The
research effort in Dr. Simons’ laboratory focuses on investigation of the role of heparin sulfate
(HS) matrix in regulation of heparin-binding growth factor signaling in endothelial cells. These
studies have been motivated by observation that one potential mechanism for regulation of
growth factor-receptor interaction is the composition of the extracellular and cell surface
proteoglycans- proteins capable of carrying HS chains that are known to be involved in heparinbinding growth factors (such as FGFs)-receptor interaction at the cell surface, as well as
accumulation and storage of these growth factors in the ECM. Modulation of HS expression on
endothelial cells may not only effect bFGF-FGF receptor interactions, but also result in alterations
of cell proliferation, migration, and adhesion. While a number of transmembrane proteins are
able to carry HS chains, one of such key HS-carrying proteins is syndecan-4. Although the
regulation of expression of syndecan-4 gene is poorly understood, one key factor involved in this
process is a macrophage-secreted peptide PR-39. Using macrophage-deficient mice, this group
has been able to show that syndecan-4 expression correlates with the appearance of bloodderived macrophages in tissues and that the extent of neovascularization in tissues correlates
with the extent of syndecan-4 expression. Studies currently in progress examine the effect of
overexpression of syndecan-4 itself in both myocytes and cardiac endothelial cells using tissuespecific promoters.
Member: JOSEPH VACANTI, M.D.
Position:
Professor of Surgery at HMS; Director, Laboratory of Transplantation and Tissue
Engineering at Children’s Hospital
Research
Area: Organ transplantation and tissue reconstruction are limited by scarcity of tissue and
organs. Dr. Vacanti is in the process of designing new tissues which are created in the lab using
functional cells plus biodegradable polymer scaffolds appropriately configured. Dr. Vacanti’s
group has studied several separate organ systems, including liver, bone, cartilage, intestine, and
urologic tissue. They have an ongoing effort that involves material science for the polymer
scaffolds, cell biology for the cell-matrix interactions, and surgical science for the implantation and
new tissue creation. The liver has been most difficult because of the severe constraints of
oxygenation and high metabolic rate of individual cells. Mild injury and hypoxia can result in
death of the cell. Therefore, a large part of this lab’s effort has been to understand this and to
optimize systems wherein sufficient cells survive for function. They have been successful in
creating new cartilage in vivo using polymeric templates combined with chonodrocytes in culture.
The cartilage is in the appropriate dimensions of the polymer template, and appears to be normal
cartilage. They have made tubes lined by enterocytes for intestinal replacement, or urothelium
for urologic reconstruction. Likewise, new bone can be formed with elements of marrow in its
center.
Member: ANTHONY WHITTEMORE, M.D.
Position: Professor of Surgery at HMS; Chief, Vascular Surgery at Brigham &
Women’s Hospital
Research Area: In collaboration with Dr. Peter Libby, Dr. Whittemore’s current investigations
include arterial dysfunction; mechanisms to clinical strategies. In collaboration with Dr. Victor
Dzau, clinical trials are in progress investigating the efficacy of pressure transfecting vein grafts
with “decoy” follicle nucleotides to minimize a smooth muscle proliferative response to
arterialization of bypass grafts. Finally, in collaboration with Dr. Michal Belkin in the Vascular
Division at Brigham & Women’s Hospital, this group is extending earlier work begun with Dr.
Lewis Shwartz in using duplex technology to access vein graft hemodynamics in an effort to
develop early predictors of graft occlusion.
Participating Faculty
Member:ALLEN D. HAMDAN, M.D.
Position: Instructor of Surgery at HMS
Research Area: Dr. Hamdan is himself a graduate of the Harvard-Longwood program. His
research explores modern methods of molecular biology to determine genetic mechanisms
involved in anastomotic intimal hyperplasia. Also molecular techniques of mRNA differential
display, sequencing, cloning, and northern blot analysis.