权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ElF4g Cleavage and Persistent Protein Synthesis Inhibition Following Ischemia

缺血后 ElF4g 裂解和持续的蛋白质合成抑制

基本信息

批准号：
7679472
负责人：
PETER Stephen VOSLER
金额：
$ 4.62万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7679472
关键词：
Affect Antibodies Binding Brain Ischemia C-terminal Calpain Calpain I Caspase Cell Death Cells Cellular Stress Response Cerebral Ischemia Cerebrum Cessation of life Clinical Complex Cysteine Protease Data Disease Eukaryotic Initiation Factor-4G Eukaryotic Initiation Factors Event Genetic Translation Glucose Goals Hour Impairment In Vitro Injury Investigation Ischemia Knockout Mice Lead Length Mediating Messenger RNA Modeling Molecular Nerve Degeneration Neurologic Neurons Oxygen Peptide Hydrolases Peptide Initiation Factors Phase Poly(A)-Binding Proteins Prevention Production Protein Binding Protein Biosynthesis Protein Synthesis Inhibition Proteins RNA Cap-Binding Proteins RNA Helicase Rattus Recombinant Proteins Recombinants Recovery Reperfusion Therapy Ribosomes Role Scaffolding Protein Site Stroke Testing Time Work base calpain inhibitor calpastatin deprivation experience in vitro Model in vivo inhibitor/antagonist interest knockout gene loss of function neuron loss neuroprotection novel novel therapeutics overexpression prevent protein degradation public health relevance research study restoration small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): The neurological complications following cerebral ischemic events (i.e. stroke) produce severe clinical disease. Our long term goal is thus to elucidate mechanisms following ischemia that produce clinical disease to potentially identify novel therapeutic strategies. Ischemia and reperfusion cause immediate and global arrest of protein synthesis in all ischemia-affected neurons. Initial protein synthesis inhibition (PSI) is either followed by near complete restoration of protein synthesis or there is a persistence of PSI. It is this persistent PSI that is highly correlated with neurodegeneration and eventual neuronal death. Thus our working hypothesis is that persistent PSI mediates cell death following cerebral ischemia. Our specific hypothesis is that proteolytic cleavage of eukaryotic initiation factor 4G (elF4G) by proteases such as calpain may mediate persistent PSI, and prevention of elF4G cleavage may block persistent PSI and thus provide neuroprotection against ischemic injury. This hypothesis is based on the following data: 1) elF4G cleavage begins prior to decreases in other protein synthesis initiation factors in vitro and in vivo, 2) the time course of cleavage is correlated with that of persistent PSI in vitro, 3) in vitro ischemia results in the production of a novel size-specific cleavage product, and 4) inhibition of calpain activity by overexpression of its endogenous inhibitor calpastatin partially restores protein synthesis following in vitro ischemia. As a result of these data, our specific focus is to determine the role of calpain in elF4G cleavage and to identify the role of elF4G cleavage in persistent PSI and cell death. Our specific aims are: 1) to test the hypothesis that elF4G cleavage and persistent PSI after in vitro ischemia is mediated by calpain activation. We will i) determine if elF4G cleavage is prevented following in vitro ischemia (i) by overexpression the endogenous calpain inhibitor calpastatin and (ii) using neurons derived from calpain knock out mice. We will also (iii) determine if prevention of elF4G cleavage via calpain inhibition can rescue protein synthesis following in vitro ischemia. 2) To test the hypothesis that prevention of elF4G cleavage alleviates persistent PSI and confers neuroprotection against in vitro ischemia. We will (i) overexpress elF4G to attempt to restore baseline elF4G levels, (ii) determine if overexpression of elF4G will confer neuroprotection following in vitro ischemia and (iii) identify the cleavage sites of elF4G by calpain using recombinant proteins in vitro. PUBLIC HEALTH RELEVANCE: Ultimately, the delineation of the mechanism governing persistent PSI may lead to a novel therapeutic strategy for cerebral ischemia.

描述（由申请人提供）：