This proposal describes a 5 year training program for the scientific and career development of a neuropathology's-scientist. The principal investigator (PI) is Assistant Professor of neuropathology at the University of Maryland, Baltimore (UMB). She will expand her skills in molecular biology, neuroscience, and preclinical models through a combination of training in cell signaling, developmental neurobiology, and laboratory models of cerebral ischemia. Specifically, the program will focus on the characterization of a novel pathway of post-ischemic neuronal apoptosis to better understand the pathogenesis of stroke. Drs. J. Marc Simard and Vladimir Gerzanich will co-mentor the PI's research and career development. Dr. Simard is an expert in neurovascular physiology and SUR1-TRPM4 channel and has mentored many physician-scientists. Dr. Gerzanich is a successful scientist with expertise in preclinical models of acute CNS disease. An advisory committee of scientists will provide additional advice regarding scientific and career development. The research proposal focuses on elucidation of a regulatory pathway activated in post-ischemic neuronal apoptosis. Through molecular biology techniques, we have identified up regulation of alpha-endosulfine (alpha Ensa) and protein co-immunoprecipitation with PP2A in stroke. We hypothesize a role for the microtubule associated serine threonine kinase-like (MASTL)-alpha Ensa-PP2A module in cdk5-mediated apoptotic cell death signaling.
The aims of this proposal include: 1) Elucidating the spatio-temporal expression of members of the MASTL-alpha Ensa-PP2A module in a rat MCAo model of stroke; 2) Demonstrating the protective effect of gene suppression of alpha Ensa on downstream effectors and neuronal apoptosis in OGD model of cultured neurons; and 3) Demonstrating the protective effect of gene suppression of alpha Ensa in a rat MCAo model of stroke.
These aims will characterize a novel role for alpha Ensa in neuronal survival and will serve as a vehicle to provide the PI with formal training and experience necessary for an independent research career focused on post-ischemic cell death signaling. The Pathology Department at UMB is an ideal setting for a career development award. The UMB Cowley Shock Trauma Center ensures access to an interdisciplinary group of scientists with expertise in ischemic brain injury and has an established history of training successful physician-scientists.

Public Health Relevance

The MASTL-alpha Ensa-PP2A module regulates cell cycle progression. Further delineation of this pathway during stroke will provide new insights regarding its role in aberrant neuronal cell cycle progression and post-ischemic cell death signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS089830-04
Application #
9333437
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Bosetti, Francesca
Project Start
2015-09-20
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Rochester
Department
Pathology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Lee, Bo Hoon; Reijnders, Margot R F; Abubakare, Oluwatobi et al. (2018) Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A 176:56-67
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Mehta, Rupal I; Tsymbalyuk, Natalia; Ivanova, Svetlana et al. (2017) ?-Endosulfine (ARPP-19e) Expression in a Rat Model of Stroke. J Neuropathol Exp Neurol 76:898-907
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Mehta, Rashi I; Mehta, Rupal I (2017) Hydrophilic Polymer Embolism: An Update for Physicians. Am J Med 130:e287-e290
Gerzanich, Volodymyr; Makar, Tapas K; Guda, Poornachander Reddy et al. (2017) Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis. J Neuroinflammation 14:177
Mehta, Rashi I; Mehta, Rupal I (2016) Polymer-induced central nervous system complications following vascular procedures: spectrum of iatrogenic injuries and review of outcomes. Hum Pathol 53:178-90
Mehta, Rashi I; Mehta, Rupal I (2016) Hydrophilic polymer embolism: past obstacles and future progress. Hum Pathol 53:191-2
Mehta, Rupal I; Mehta, Rashi I; Choi, Julia M et al. (2015) Hydrophilic polymer embolism and associated vasculopathy of the lung: prevalence in a retrospective autopsy study. Hum Pathol 46:191-201

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