Alpha-Endosulfine in Post-Ischemic Neuronal Apoptosis

α-硫辛在缺血后神经元凋亡中的作用

基本信息

批准号：
9119209
负责人：
Rupal I. Mehta
金额：
$ 15.41万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-20 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9119209
关键词：
Acute Advisory Committees Animals Apoptosis Apoptotic Autopsy Baltimore Binding Brain Hypoxia-Ischemia Cause of Death Cell Culture Techniques Cell Cycle Progression Cell Death Cell Death Signaling Process Cell Nucleus Cells Central Nervous System Diseases Cerebral Ischemia Cessation of life Cleaved cell Co-Immunoprecipitations Cyclin-Dependent Kinase 5 Economics Ensure Genes Glucose H2 gene Health Homologous Gene Human Immunoblotting Immunohistochemistry In Situ Hybridization Individual Infarction Infusion procedures Ipsilateral Ischemia Ischemic Brain Injury K-Series Research Career Programs Laboratories Maryland Mediating Mentors Messenger RNA Microtubules Middle Cerebral Artery Occlusion Mitosis Mitotic Modeling Molecular Molecular Biology Molecular Biology Techniques Molecular Target Neurons Neurosciences Nuclear Nuclear Translocation Oxygen Pathogenesis Pathology Pathway interactions Pattern Phosphoproteins Phosphoric Monoester Hydrolases Phosphorylation Physicians Physiology Pre-Clinical Model Principal Investigator Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Protein-Serine-Threonine Kinases Proteins Rattus Recording of previous events Regulation Regulatory Pathway Research Research Proposals Role Scientist Shock Signal Transduction Small Interfering RNA Stroke TP53 gene Tissues Training Training Programs Universities Up-Regulation Yeasts alpha-endosulfine base career career development caspase-3 deprivation developmental neurobiology disability endosulfine experience human tissue in vivo insight member neuron apoptosis neuron loss neuronal survival neuropathology novel prevent professor programs protective effect research and development research study skills trauma centers

项目摘要

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.

描述（由申请人提供）：该提案描述了针对神经病理学科学家的科学和职业发展的为期 5 年的培训计划。首席研究员 (PI) 是巴尔的摩马里兰大学 (UMB) 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方面的培训相结合，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，该计划将重点关注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。博士。 J. Marc Simard 和 Vladimir Gerzanich 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 SUR1-TRPM4 通道方面的专家，并指导过许多医师科学家。 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。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 α-硫辛 (α Ensa) 的上调以及与 PP2A 的蛋白质免疫共沉淀在中风中的作用。我们假设微管相关丝氨酸苏氨酸激酶样 (MASTL)-α Ensa-PP2A 模块在 cdk5 介导的细胞凋亡信号传导中发挥作用。该提案的目的包括： 1) 阐明 MASTL-alpha Ensa-PP2A 模块成员在大鼠 MCAo 中风模型中的时空表达； 2）在培养神经元的OGD模型中证明αEnsa基因抑制对下游效应器和神经元凋亡的保护作用； 3) 在大鼠 MCAo 中风模型中证明 α Ensa 基因抑制的保护作用。这些目标将体现 alpha 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 病理学系是获得职业发展奖的理想场所。 UMB 考利休克创伤中心确保能够接触到具有缺血性脑损伤专业知识的跨学科科学家小组，并拥有培训成功的医师科学家的悠久历史。