Marianne R. Smith, Ph.D.
4128 Natural Sciences II, University of California, Irvine, Irvine, CA 92697
Tel: (949) 824-2013
e-mail: mrsmith1@uci.edu
Work Experience
5/15/13-current
Research Development Officer for the School of Biological Sciences
(Office of Research, University of California, Irvine)
I manage the preparation and submission of multi-investigator grant
proposals often involving scientists from many different departments
across campus. I organize and lead meetings to discuss preparation of the
proposal, develop a project timeline and ensure that each component of
the grant proposal is prepared on time. I write draft letters of support for
deans, vice chancellors, and the chancellor, edit the proposal for both
scientific content and clarity, work with the Office of Institutional Research
to acquire and compile any required institutional data, and work with
Sponsored Projects Administration to ensure that all aspects of the
proposal meet compliance with the funding organization and UCI
regulations.
3/1/11-5/14/13
Assistant Project Scientist (Laboratory of Dr. J. Lawrence Marsh,
University of California, Irvine)
I studied the protein, Sir2 (SIRT1 in mammals), which is a Class III
Deacetylase. Sir2 has been shown to be neuroprotective in Huntington’s
disease (HD) when its levels are genetically reduced in the Drosophila
model of HD. Very few pharmacologic tools are available to manipulate
this protein’s activity. I evaluated a promising new SIRT1 inhibitor,
selisistat, and found that it specifically inhibits Sir2 in vivo to partially
restore neurodegeneration in the eye of HD Drosophila. If Sir2 is knocked
out genetically, selisistat is no longer able to protect against
neurodegeneration in HD. I also determined that Sir2 inhibition does not
affect protein clearance or acetylation of the mutant Huntingtin protein in
larvae.
9/01/06-2/28/11
I did not work during this time period due to child rearing.
10/16/00-8/31/06
Content Scientist II (Ingenuity Systems Incorporated)
I entered information from molecular and cellular biology based
scientific journal articles into the Ingenuity Systems database by selecting,
classifying, and structuring information into a specific format. After 6
months, I was promoted to review information entered by other Ph.D.
scientists. I made entry corrections and/or provided feedback to the
scientists, guiding them to make changes and addressing questions to
minimize future errors.
1/1/99-10/15/00
Post Doctoral Fellow (Laboratory of Dr. Sascha du Lac, The Salk
Institute
for
Biological
Sciences,
Systems
Neurobiology
Laboratories)
The adaptation of behavioral reflexes, termed behavioral gain, can
be modified by experience via mechanisms that are largely unknown.
Within the circuitry for the vestibulo-ocular reflex (VOR), neurons in the
medial vestibular nucleus (MVN) show adaptive changes in firing rate
responses that are correlated with VOR gain. I examined the contributions
of calcium-dependent currents to firing responses in MVN neurons
recorded with whole cell patch electrodes in rodent brainstem slices in
vitro. I discovered that blockade of SK calcium-activated potassium
channels occlude gain increases through N-type calcium channels, while
blocking BK calcium-activated potassium channels occlude gain increases
through T type calcium channels. I also used histology and confocal
microscopy to examine brain slices of GFP mice and identify specific
characteristics of MVN neurons involved in the adaptive response. In
addition, I helped teach and supervise graduate and undergraduate
research students.
I also presented seminars to the Systems
Neurobiology Department and presented abstract poster presentations at
major scientific meetings.
9/1/93-8/28/98
Graduate Student (Laboratory of Dr. Alan Goldin University of
California, Irvine, Department of Physiology and Biophysics)
I examined regions of the rat brain sodium channel that are
important for fast inactivation. Sodium channel inactivation occurs through
hydrophobic interactions between the inactivation particle formed by the
III-IV linker and a putative docking site. I mutated amino acids in the S4S5 linkers of the sodium channel to identify residues that form the docking
site for the fast inactivation particle. I injected sodium channel mRNA into
Xenopus oocytes and examined the electrophysiological properties of the
wild-type and mutant channels using two-electrode voltage clamp, cutopen oocyte clamp, and inside-out patch clamp techniques. I determined
that a charged residue substituted for A1329 in the IIIS4-S5 linker of the
sodium channel disrupts inactivation. Combining this mutation with an
opposite, compensatory charge mutation in the inactivation particle
restored inactivation. To study the physiological effects of disrupted
inactivation, I created a mutant sodium channel with minor disruption of
inactivation and placed the construct downstream of the neuron specific
enolase promoter to specify expression in the brains of transgenic mice.
These mice exhibited focal seizures in the hippocampus with a tonic
deviation of the head and body.
1993
Undergraduate Research (Scripps Clinic and Research Foundation,
La Jolla, CA)
I examined by electrophysiology the pharmacological effects of a variety of
drugs on action potentials, EPSPs, and AHPs of neurons in the rat
hippocampus.
1992
Undergraduate Research (UCSD Medical Center, San Diego, CA)
I investigated the effect of mitral regurgitation on pulmonary venous flow in
an in vitro model of the left atrium.
1988
Computer Programmer (Quantex, Sunnyvale, CA)
I wrote a small library of image processing routines that was included with
the Quantex software development system.
Education
1993-1998
University of California, Irvine
Department of Physiology and Biophysics
Ph.D. in Biological Sciences, August 1998
Advisor: Alan L. Goldin, M.D., Ph.D.
Thesis: “Functional Analysis of Sodium Channel Inactivation and Its
Physiological Significance in the Central Nervous System”
1988-1993
University of California, San Diego
B.S., Biophysics
Publications
Mizushige, K., Shiota, T., Paik, J., Griever, G., Depp, M.R., Passafini, A., Shandas, R.,
DeMaria, A.N., and Sahn, D.J. Effects of Pulmonary Venous Flow Direction on Mitral
Regurgitation Jet Area as Imaged by Color Doppler Flow Mapping: An in vitro Study.
Circulation, Mar 1995, 91(6):1834-1839.
Passafini, A., Shiota, T., Depp, M.R., Paik, J., Ge, S., Shandas, R., Sahn, D.J. Factors
Influencing Pulmonary Venous Flow Velocity Patterns in Mitral Regurgitation: An in vitro Study.
J Am Coll Cardiol, Nov. 1995, 26(5):1333-1339.
Kohrman, D.C., Smith, M.R., Goldin, A.L., Harris, J., Meisler, M.H. A Missense Mutation in the
Sodium Channel Scn8a Is Responsible for Cerebellar Ataxia in the Mouse Mutant jolting. J.
Neuro. Sci., Oct. 1996, 16(19):5993-5999.
Smith, M.R. and Goldin, A.L. Interaction Between the Sodium Channel Inactivation Linker and
Domain III S4-S5. Biophysical Journal, October 1997, 73:1885-1895.
Smith, M.R., Smith, R.D., Plummer, N.W., Meisler, M.H., and Goldin, A.L., Functional Analysis
of the Mouse Scn8a Sodium Channel, J. Neuro. Sci., August 1998, 18(16): 6093-6102.
Smith, M.R. and Goldin, A.L. A Mutation that Causes Ataxia Shifts the Voltage-Dependence
of the Scn8a Sodium Channel. NeuroReport, September 1999, 10:1-5.
Kearney, J.A., Plummer, N., Smith, M.R., Kapur, J., Cummins, T.R., Waxman, S.G., Goldin,
A.L., and Meisler, M.H. A Gain-of-function Mutation in the Sodium Channel Gene Scn2a
Results in Seizures and Behavioral Abnormalities. Neuroscience, 2001, 102(2): 302-317.
Smith, M.R., Nelson, A.B., and du Lac, S. Regulation of Firing Response Gain by Calciumdependent Mechanisms in Vestibular Nucleus Neurons. Journal of Neurophysiology, April
2002, 87: 2031-2042.
Song, W.*, Smith, M.R.*, Syed, A., Lukacsovich, T., Barbaro, B.A., Purcell, J., Bornemann,
D.J., Burke, J., and Marsh, J.L.
Morphometric Analysis of Huntington’s Disease
Neurodegeneration in Drosophila. Tandem Repeats in Genes, Proteins, and Disease, edited
by Tony Hannan and Danny Hatters. In press. (* Authors contributed equally.)
Smith, M.R., Syed, A., Lukacsovich, T., Purcell, J., Barbaro, B., Worthge, S.A., Wei, S.R.,
Pollio, G., Magnoni, L., Scali, C., Massai, L., Franceschini, D., Camarri, M., Gianfriddo, M.,
Diodato, E., Thomas, R., Gokce, O., Tabrizi, S.J., Caricasole, A., Landwehrmeyer, B.,
Menalled, L., Murphy, C., Ramboz, S., Luthi-Carter, R., Westerberg, G., Marsh, J.L. A potent
and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of
Huntington’s disease. Hum. Mol. Genet., In press.
Presentations
1996 Biophysical Society Annual Meeting (Baltimore, MD)
Title: “Probing S4-S5 Regions of the Rat Brain Sodium Channel for the Fast Inactivation
Particle Receptor Site”, M.R. Smith and A.L. Goldin.
1997 Biophysical Society Annual Meeting (New Orleans, LA)
Title: “Interaction Between the Putative Sodium Channel Inactivation Particle and
Domain III S4-S5”, M.R. Smith and A.L Goldin.
1998 Society for Neuroscience Annual Meeting (Los Angeles, CA)
Title: “Functional Analysis of the Mouse Scn8a Sodium Channel”, M.R. Smith, R.D.
Smith, N.W. Plummer, M.H. Meisler, and A.L. Goldin.
1999 Society for Neuroscience Annual Meeting (Miami, Florida)
Title: "Cellular Mechanisms of Gain Control in Medial Vestibular Nucleus Neurons",
M.R. Smith, D.L. Ruderman, S. du Lac.
2012 CHDI Sponsored HD Therapeutics Conference (Palm Springs, CA)
Title: “Inhibition by Selisistat Alleviates Pathology in Multiple Animal and Cell Models of
Huntington’s Disease,” M.R. Smith, J. Burke, T. Lukacsovich, B. Barbaro, J.M. Purcell,
D. Franceschini, E. Diodato, C. Scali, L. Massai, R. Thomas, L. Magnoni, O. Gokce, T.
Seredenina, S.J. Tabrizi, G. Westerberg, G. Gaviraghi, R. Luthi-Carter, A. Caricasole
and J.L. Marsh
Awards
1988
1996
2000
2011
Society for Women Engineers Scholarship Award
Biophysical Society Travel Award
National Research Service Award (3 year Postdoctoral Fellowship)
NIH Research Supplement to Promote Re-Entry into Biomedical Research Careers (2
year Fellowship)