Heat shock proteins in brain ischemia and stroke

脑缺血和中风中的热休克蛋白

基本信息

批准号：
9206066
负责人：
Midori A Yenari
金额：
--
依托单位：
VETERANS AFFAIRS MED CTR SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2019-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9206066
关键词：
ATP phosphohydrolase Address Animals Apoptosis Apoptotic BCL2 gene Binding Brain Brain Ischemia CD95 Antigens Caspase Cell Death Cell membrane Cell surface Cessation of life Clathrin Collaborations Dictyostelium discoideum dynamin A Disease Dynamin Dynamin I Endocytosis Genetic Transcription Glucose Golgi Apparatus Guanosine Triphosphate Phosphohydrolases Heat shock proteins Heat-Shock Proteins 70 In Vitro Inflammation Injury Interruption Ischemia Knock-out Knockout Mice Korea Lead Link Mediating Mitochondria Modeling Molecular Chaperones NF-kappa B Nature Neurons Oxygen Pharmacology Prevention Property Protein Family Proteins Proteomics Regulation Resistance Role Stroke Surface Therapeutic Therapeutic Effect Transgenic Animals Transgenic Organisms Tumor Necrosis Factor Ligand Superfamily Member 6 Universities Veterans Work brain cell cytochrome c deprivation improved outcome in vivo Model inhibitor/antagonist member neuroprotection overexpression prevent protein aggregation protein folding public health relevance receptor mediated endocytosis therapeutic target trafficking uptake

ATP phosphohydrolase Address Animals Apoptosis Apoptotic BCL2 gene Binding Brain Brain Ischemia CD95 Antigens Caspase Cell Death Cell membrane Cell surface Cessation of life Clathrin Collaborations Dictyostelium discoideum dynamin A Disease Dynamin Dynamin I Endocytosis Genetic Transcription Glucose Golgi Apparatus Guanosine Triphosphate Phosphohydrolases Heat shock proteins Heat-Shock Proteins 70 In Vitro Inflammation Injury Interruption Ischemia Knock-out Knockout Mice Korea Lead Link Mediating Mitochondria Modeling Molecular Chaperones NF-kappa B Nature Neurons Oxygen Pharmacology Prevention Property Protein Family Proteins Proteomics Regulation Resistance Role Stroke Surface Therapeutic Therapeutic Effect Transgenic Animals Transgenic Organisms Tumor Necrosis Factor Ligand Superfamily Member 6 Universities Veterans Work brain cell cytochrome c deprivation improved outcome in vivo Model inhibitor/antagonist member neuroprotection overexpression prevent protein aggregation protein folding public health relevance receptor mediated endocytosis therapeutic target trafficking uptake

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项目摘要

DESCRIPTION (provided by applicant): Stroke is a common affliction among veterans, and treatments are few. Work by our labs and those of our collaborators' have focused on the protective potential of heat shock proteins, namely, the highly inducible 70 kD heat shock protein (HSP70). HSP70 appears to have cytoprotective properties by nature of its chaperone functions, presumably leading to enhancement of nascent protein folding and prevention of protein aggregation. However, work in related fields has shown that HSPs appear to positively influence many aspects of ischemic cell death. We previously showed that overexpression of HSP70 or its pharmacological induction protects by inhibiting inflammation and upregulating the anti-apoptotic protein, Bcl-2. Others have shown the HSP70 blocks apoptosis by preventing cytochrome c release from the mitochondria or inhibiting caspase activation. Through collaborative work with Dr. Jong Eun Lee (Yonsei University, S. Korea), we identified dynamin as one protein substantially suppressed by HSP70 overexpression. Dynamin is a GTPase involved in receptor- mediated endocytosis through detaching clathrin-coated vesciles from the plasma membrane. Its role in ischemic brain cell death is completely unknown, but has been implicated in facilitating apoptosis by trafficking the death receptor Fas to the cell surface. In this application, we propose to further explore these observations that HSP70 protects the brain against stroke by interfering with dynamin export of Fas, and to address the implications of dynamin as a therapeutic target. Specific aim 1: Determine whether dynamin inhibition is protective, and if its suppression is linked to protection by HSP70. Specific aim 2: Determine whether there is a link between dynamin, fas and dynamin inhibition by HSP70. Specific aim 3: Determine how HSP70 regulates dynamin expression and/or function.

描述（由申请人提供）：中风是退伍军人中常见的苦难，而治疗很少。我们的实验室和合作者的工作集中在热休克蛋白的保护潜力上，即高度诱导的70 kD热休克蛋白（HSP70）。 HSP70的伴侣功能本质上具有细胞保护特性，可能导致了新生蛋白质折叠的增强并预防蛋白质聚集。但是，在相关领域的工作表明，HSP似乎对缺血性细胞死亡的许多方面产生积极影响。我们先前表明，HSP70或其药理诱导的过表达通过抑制炎症和上调抗凋亡蛋白Bcl-2来保护。其他人通过防止细胞色素c从线粒体释放或抑制caspase激活来阻止HSP70阻断凋亡。通过与Jong Eun Lee博士（S. Yonsei University，S。韩国）的合作工作，我们确定Dynamin是HSP70过表达的一种蛋白质。 Dynamin是一种通过从质膜上脱离网状蛋白涂层的vesciles来参与受体介导的内吞作用的GTPase。它在缺血性脑细胞死亡中的作用是完全未知的，但与通过将死亡受体FAS运送到细胞表面来促进凋亡有关。在此应用中，我们建议进一步探索这些观察结果，即HSP70通过干扰Dynamin的FAS出口，并解决Dynamin作为治疗靶点的含义，从而保护大脑免受中风的影响。特定目标1：确定动力学抑制是否具有保护性，以及其抑制是否与HSP70的保护有关。特定目标2：确定HSP70的Dynamin，Fas和Dynamin抑制之间是否存在联系。特定目标3：确定HSP70如何调节动力学表达和/或功能。