Alpha-Endosulfine in Post-Ischemic Neuronal Apoptosis

描述(由申请人提供)：本建议书描述了一项为期5年的神经病理学科学家的科学和职业发展培训计划。首席研究员(PI)是巴尔的摩马里兰大学(UMB)的神经病理学助理教授。她将通过细胞信号、发育神经生物学和脑缺血实验室模型的培训相结合的方式，扩展她在分子生物学、神经科学和临床前模型方面的技能。具体地说，该计划将专注于表征缺血后神经元凋亡的新途径，以更好地了解中风的发病机制。J.Marc Simard博士和Vladimir Gerzanich博士将共同指导PI的研究和职业发展。西马德博士是神经血管生理学和SUR1-TRPM4通道方面的专家，曾指导过许多内科科学家。Gerzanich博士是一位成功的科学家，在急性中枢神经系统疾病的临床前模型方面拥有专业知识。一个由科学家组成的咨询委员会将就科学和职业发展提供额外的建议。该研究计划侧重于阐明在缺血后神经元凋亡中激活的调节通路。通过分子生物学技术，我们已经发现在卒中中α-内硫醚(α-Ensa)的上调以及蛋白与PP2A的免疫共沉淀。我们假设微管相关的丝氨酸苏氨酸激酶样(MAST1)-αEnsa-PP2A模块在CDK5介导的细胞死亡信号中起到了作用。该建议的目的包括：1)阐明Mast1-αEnsa-PP2A模块成员在卒中大鼠MCAO模型中的时空表达；2)证明αEnsa基因抑制对OGD培养神经元模型中下游效应和神经元凋亡的保护作用；以及3)证明αEnsa基因抑制对卒中大鼠MCAO模型的保护作用。这些目标将表征阿尔法Ensa在神经元存活中的新角色，并将作为一种载体，为PI提供正式培训和必要的经验，以便从事专注于缺血后细胞死亡信号的独立研究。UMB的病理学系是职业发展奖的理想场所。UMB考利休克创伤中心确保接触到具有缺血性脑损伤专业知识的跨学科科学家小组，并拥有培训成功的内科科学家的既定历史。

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.