Mitochondrial Unfolded Proteins and Cell Degeneration

线粒体未折叠蛋白和细胞变性

基本信息

批准号：
7116821
负责人：
Cole M Haynes
金额：
$ 4.88万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7116821
关键词：
Caenorhabditis elegans RNA interference SDS polyacrylamide gel electrophoresis biological signal transduction cell cell interaction endoplasmic reticulum gene expression intercellular connection mitochondria neural degeneration pathologic process postdoctoral investigator protein folding

项目摘要

DESCRIPTION (provided by applicant): The capacity to fold and assemble nascent unfolded proteins and to degrade unassembled and misfolded proteins is important to organelle homeostasis and is regulated by unfolded protein responses activated by specific stress signals. Defects in mitochondrial protein folding play a role in important neurological diseases such as spastic paraplegia and Parkinson's disease. My goal is to understand how mitochondria regulate their ability to fold and process proteins in response to variations in unfolded protein load. I will identify genes required for signaling the mitochondrial unfolded protein response by a systematic, sequential, genome-wide survey for C. elegans genes whose inactivation by RNAi impairs the mitochondrial unfolded protein response. I will prioritize and validate the genes identified in this survey based on biochemical assays that measure mitochondrial protein folding capacity, degradation capacity and import capacity in living C. elegans. Finally I will seek to identify the mode of action of genes that signal the mitochondrial unfolded protein response. By understanding the basic principles of signaling from the mitochondria to the nucleus I expect to provide insight into pathophysiological processes involved in neurodegeneration.

描述（申请人提供）：折叠和组装新生展开的蛋白质并降解未组装和错误折叠的蛋白质的能力对于细胞器稳态很重要，并且受特定应力信号激活的未折叠蛋白反应调节。线粒体蛋白折叠的缺陷在重要的神经系统疾病中起作用，例如痉挛性截瘫和帕金森氏病。我的目标是了解线粒体如何调节其折叠和处理蛋白质的能力，以响应未折叠的蛋白质负荷的变化。我将通过对秀丽隐杆线虫基因的系统，顺序的，全基因组的调查来确定对线粒体展开的蛋白质反应信号所需的基因，而秀丽隐杆线虫基因的失活会损害线粒体展开的蛋白质反应。我将根据测量线粒体蛋白质折叠能力，降解能力和进口能力的生物化学测定法对本调查中确定的基因进行优先级和验证。最后，我将寻求确定信号线粒体展开的蛋白质反应的基因的作用方式。通过了解从线粒体到核的信号传导的基本原理，我希望能够深入了解与神经变性有关的病理生理过程。