Alpha-Endosulfine in Post-Ischemic Neuronal Apoptosis

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于神经病理学科学家的科学和职业发展。主要研究者（PI）是巴尔的摩马里兰州大学（UMB）的神经病理学助理教授。她将通过细胞信号传导，发育神经生物学和脑缺血实验室模型的组合培训来扩展她在分子生物学，神经科学和临床前模型方面的技能。具体来说，该计划将集中在缺血后神经元凋亡的新途径的表征，以更好地了解中风的发病机制。J. Marc Simard博士和弗拉基米尔Gerzanich博士将共同指导PI的研究和职业发展。Simard博士是神经血管生理学和SUR 1-TRPM 4通道的专家，并指导了许多医生科学家。Gerzanich博士是一位成功的科学家，擅长急性CNS疾病的临床前模型。一个科学家咨询委员会将提供有关科学和职业发展的额外建议。该研究计划的重点是阐明在缺血后神经元凋亡中激活的调节途径。通过分子生物学技术，我们已经确定了上调α-内皮素（α Ensa）和蛋白质免疫共沉淀与PP 2A在中风。我们假设微管相关丝氨酸苏氨酸激酶样（MASTL）-α Ensa-PP 2A模块在cdk 5介导的凋亡细胞死亡信号传导中的作用。该提案的目的包括：1）阐明MASTL-α Ensa-PP 2A模块成员在大鼠MCAo中风模型中的时空表达; 2）证明α Ensa基因抑制对培养神经元的OGD模型中下游效应子和神经元凋亡的保护作用; 3）证明α Ensa基因抑制对大鼠MCAo中风模型的保护作用。这些目标将表征α Ensa在神经元存活中的新作用，并将作为一种工具，为PI提供专注于缺血后细胞死亡信号传导的独立研究生涯所需的正式培训和经验。UMB的病理学系是职业发展奖的理想场所。UMB Cowley休克创伤中心确保获得具有缺血性脑损伤专业知识的跨学科科学家小组，并拥有培训成功的医生科学家的悠久历史。

DESCRIPTION (provided by applicant): 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.