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.
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.
|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|
|Mehta, Rashi I; Mehta, Rupal I (2018) Hydrophilic Polymer Embolism: Implications for Manufacturing, Regulation, and Postmarket Surveillance of Coated Intravascular Medical Devices. J Patient Saf :|
|Mehta, Rashi I; Perrin, Richard J; Baldzizhar, Raman et al. (2017) Polymer Coating Embolism: Cause of Cerebral Vasculopathy and Death following Congenital Heart Repair in Two Infants. J Neuropathol Exp Neurol 76:978-980|
|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|
|Mestre, Humberto; Kostrikov, Serhii; Mehta, Rupal I et al. (2017) Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clin Sci (Lond) 131:2257-2274|
|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; Chun, Youngjae (2015) Hydrophilic polymer embolism: an underrecognized iatrogenic cause of ischemia, inflammation, and coagulopathy. Hum Pathol 46:488-9|
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