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Elucidating the mechanism of action of novel ClpP activators in activation of the mitochondrial unfolded protein response.

阐明新型 ClpP 激活剂在激活线粒体未折叠蛋白反应中的作用机制。

基本信息

批准号：
10416057
负责人：
Lee M Graves
金额：
$ 31.44万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10416057
关键词：
Affect Aging Agonist Alzheimer&apos s Disease Antineoplastic Agents Applications Grants Ataxia Binding Biological Biological Process Breast Caenorhabditis elegans Cell Energetics Cell Line Cell Nucleus Cell physiology Cells Cellular Metabolic Process Cellular Stress Cellular biology Chemicals Citric Acid Cycle Clinical Trials Consumption Data Degenerative Disorder Disease Dose Endometrial Endoplasmic Reticulum Event Generations Genetic Genetic Translation Glioblastoma Glucose Glutamine Glycolysis Goals Growth Homeostasis Human Impairment Investigation Knock-out Link Lower Organism Malignant Neoplasms Mammalian Cell Measures Metabolic Metabolism Mitochondria Mitochondrial Matrix Mitochondrial Proteins Modification Molecular Nuclear Parkinson Disease Pathway interactions Peptide Hydrolases Peptides Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Play Polyribosomes Process Production Property Protein Biosynthesis Protein Synthesis Induction Protein Synthesis Inhibition Proteins Proteome Proteomics Regulation Research Respiratory Chain Ribosomal Proteins Role Scientist Signal Pathway Signal Transduction Stress Time VDAC1 gene Western Blotting Work analog anti-cancer arm biological adaptation to stress cell growth drug development drug mechanism experimental study insight interest leukemia metabolomics misfolded protein mitochondrial metabolism mutant neoplastic cell news novel novel therapeutics protein degradation proteostasis proteotoxicity response sensor small molecule stable isotope tool transcription factor CHOP

项目摘要

The mitochondrial Unfolded Protein Response (UPRMT) is a highly conserved stress pathway that when dysregulated is causally connected to a host of degenerative diseases including Parkinsons, Alzheimers, Freiderichs Ataxia and aging. The recent identification of components in the UPRMT has stimulated interest in this as a “druggable” pathway. Central to the UPRMT is the mitochondrial protease ClpP, required for the turnover of damaged and misfolded proteins in response to cellular stresses. We and others recently identified ClpP as an unexpected target for a novel class of anti-cancer compounds known as imipridones (ONC201) and related analogs (https://www.the-scientist.com/news-opinion/found--a-cancer-drugs-mechanism-of-action- 65918). We showed that these compounds activated ClpP and the UPRMT as determined by the degradation of mitochondrial proteins, impaired mitochondrial respiratory chain activity, and increased integrated stress response (ISR) proteins (CHOP/ATF4). Thus, the main objective of this research is to investigate the basic mechanisms of the UPRMT and elucidate how drug- induced activation of ClpP initiates important stress signals that regulate cell growth and metabolism. We propose three aims to accomplish this: in Aim 1 we will use comprehensive proteomics approaches to identify ClpP substrates and peptides released from the mitochondria. In Aim 2 we will determine how ClpP activation dysregulates mitochondrial metabolism, and affects the consumption of glucose and glutamine by glycolysis and the TCA cycle. In Aim 3 we will determine how ClpP activation alters cytosolic signaling events, namely the activation of the ISR and the resulting reduction in protein synthesis. If successful, our studies will provide significant new insight into the biological functions of the UPRMT and how ClpP regulates this pathway functions to modulate cell stress in normal and disease states.

线粒体未折叠蛋白反应（UPRMT）是一种高度保守的应激途径，当失调与许多退行性疾病有因果关系时，包括帕金森病、阿尔茨海默病、弗里德里希共济失调和衰老。最近识别的组件 UPRMT 的研究激起了人们对此作为“可成药”途径的兴趣。 UPRMT 的核心是线粒体蛋白酶 ClpP，是受损和错误折叠蛋白质周转所必需的对细胞应激的反应。我们和其他人最近将 ClpP 确定为一个意想不到的目标一类新型抗癌化合物，称为亚咪酮 (ONC201) 和相关类似物（https://www.the-scientist.com/news-opinion/found--a-cancer-drugs-mechanism-of-action- 65918）。我们证明这些化合物激活 ClpP 和 UPRMT，如通过线粒体蛋白质降解，线粒体呼吸链活性受损，增加综合应激反应 (ISR) 蛋白 (CHOP/ATF4)。因此，主要目标是本研究旨在调查 UPRMT 的基本机制并阐明药物如何 ClpP 的诱导激活引发重要的应激信号，调节细胞生长和代谢。我们提出三个目标来实现这一目标：在目标 1 中，我们将使用全面的蛋白质组学方法鉴定 ClpP 底物和线粒体释放的肽。在目标 2 中，我们将确定 ClpP 激活如何失调线粒体代谢，以及影响糖酵解和 TCA 循环对葡萄糖和谷氨酰胺的消耗。在目标 3 中，我们将决定 ClpP 激活如何改变胞质信号传导事件，即 ISR 以及由此导致的蛋白质合成减少。如果成功的话，我们的研究将提供对 UPRMT 的生物学功能以及 ClpP 如何调节它的重要新见解通路的功能是调节正常和疾病状态下的细胞应激。