The COP9 SIgnalosome in the Heart

COP9 心脏中的信号体

基本信息

批准号：
8457106
负责人：
XUEJUN WANG
金额：
$ 34.48万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457106
关键词：
American Attenuated Autophagocytosis Autophagosome Cardiac Cardiac Myocytes Cardiac ablation Cause of Death Cell Death Cessation of life Chronic Clinical Management Congestive Heart Failure Cullin Proteins Data Degradation Pathway Diagnosis Dilated Cardiomyopathy Disease Dominant-Negative Mutation Excision Figs - dietary Foundations Functional disorder Genes Genetic Goals Healthcare Heart Heart Diseases Impairment Infusion procedures Knock-out Knockout Mice Life Link Measures Mediating Messenger RNA Molecular Mus Necrosis Organelles Pathway interactions Perinatal Phenotype Phosphotransferases Proteasome Inhibition Proteins Proteolysis Quality Control RIPK3 gene Regulation Research Research Project Grants Role Syndrome System Testing Transgenic Mice Transgenic Organisms Ubiquitin Work aged base disability fighting genetic manipulation heart function improved innovation multicatalytic endopeptidase complex novel novel therapeutics overexpression premature prevent protein complex protein misfolding ubiquitin-protein ligase

American Attenuated Autophagocytosis Autophagosome Cardiac Cardiac Myocytes Cardiac ablation Cause of Death Cell Death Cessation of life Chronic Clinical Management Congestive Heart Failure Cullin Proteins Data Degradation Pathway Diagnosis Dilated Cardiomyopathy Disease Dominant-Negative Mutation Excision Figs - dietary Foundations Functional disorder Genes Genetic Goals Healthcare Heart Heart Diseases Impairment Infusion procedures Knock-out Knockout Mice Life Link Measures Mediating Messenger RNA Molecular Mus Necrosis Organelles Pathway interactions Perinatal Phenotype Phosphotransferases Proteasome Inhibition Proteins Proteolysis Quality Control RIPK3 gene Regulation Research Research Project Grants Role Syndrome System Testing Transgenic Mice Transgenic Organisms Ubiquitin Work aged base disability fighting genetic manipulation heart function improved innovation multicatalytic endopeptidase complex novel novel therapeutics overexpression premature prevent protein complex protein misfolding ubiquitin-protein ligase

展开

项目摘要

DESCRIPTION (provided by applicant): Dysfunction of the ubiquitin-proteasome system (UPS) and autophagy, two main intracellular proteolytic pathways, have been observed in a variety of heart diseases and implicated in the genesis of congestive heart failure (CHF), the final common pathway for virtually all heart diseases and afflicting the life of millions of Americans. The COP9 signalosome (CSN) is an evolutionarily conserved protein complex consisting of 8 unique subunits (CSN1 ~ CSN8). In the preceding competitive cycle, we have discovered that the Csn8/CSN is required for not only UPS-mediated proteolysis but also autophagy to exert their protein quality control roles in mouse hearts. Perinatal cardiomyocyte-restricted CSN subunit 8 knockout (CR-Csn8KO) causes primarily massive cardiomyocyte (CM) necrosis in intact mice and this is preceded by impairment in the autophagic- lysosomal pathway and accompanied by UPS malfunction. The CR-Csn8KO mice develop dilated cardiomyopathy and die of CHF prematurely. Building upon these exciting novel findings, we propose to decipher the molecular mechanisms by which Csn8/CSN regulates the autophagic-lysosomal pathway and cardiomyocyte survival in the heart. Using a combination of innovative genetic manipulations and pharmacological interrogations in intact mice, we will pursue three specific aims to test the central hypothesis that Csn8/CSN promotes AM via Rab7 and facilitates PQC in CMs, thereby promoting CM survival by suppressing the RIP1/RIP3-mediated necrosis pathway. Specific aim 1 defines molecular mechanisms by which Csn8/CSN promotes autophagy. This will test the hypothesis that Csn8/CSN regulates autophagosome maturation (AM) via Rab7. Specific aim 2 investigates the pathophysiological significance of autophagic activation by proteasome inhibition. This is to test the hypothesis that proteasome functional insufficiency (PFI) activates cardiac autophagy and this activation compensates for protein quality control impairment caused by PFI. Specific aim 3 tests the hypotheses that impaired AM compromises the degradation of proteasome substrates and that the duo-impairment in the UPS and autophagy triggers CM necrosis via the RIP1-RIP3 mediated pathway. The completion of this research is expected to significantly improve our understanding on how protein quality control and degradation pathways in the heart are coordinately regulated, especially by the CSN, which will facilitate the search for new strategies to prevent and/or more effectively treat CHF, a leading cause of death and disability in the US.

描述（由申请人提供）：在多种心脏病中观察到了泛素蛋白 - 蛋白酶体系统（UPS）和自噬的功能障碍，这是两种主要的细胞内蛋白水解途径，并参与了各种心脏病的生成（CHF）的生成（CHF），这是针对美国全心全意疾病的最终共同途径，是全心疾病的最终公共路径，使美国的生活和米尔群岛的生命与Millions and Millions and Millions and Millions and Millions and Millions。 COP9信号体（CSN）是一种进化保守的蛋白质复合物，由8个独特的亚基（CSN1〜CSN8）组成。在前面的竞争周期中，我们发现CSN8/CSN不仅需要UPS介导的蛋白水解，而且还需要自噬才能在小鼠心脏中发挥其蛋白质质量控制作用。围产期心肌细胞限制的CSN亚基8基因敲除（CR-CSN8KO）主要是完整小鼠中主要是大规模的心肌细胞（CM）坏死，这是自噬 - 肌瘤途径的损害，并伴有UPS功能不全。 CR-CSN8KO小鼠会出现扩张的心肌病，过早地死于CHF。在这些令人兴奋的新发现的基础上，我们建议破译CSN8/CSN调节心脏中自噬溶质体途径和心肌细胞存活的分子机制。使用完整小鼠中创新的遗传操作和药理学询问的结合，我们将追求三个特定的目标，以测试CSN8/CSN通过RAB7促进AM的中心假设，并促进CMS中的PQC，从而通过抑制RIP1/RIP3/RIP3介导的Necrise pation促进CM生存。特定目标1定义了CSN8/CSN促进自噬的分子机制。这将检验以下假设：CSN8/CSN通过RAB7调节自噬体成熟（AM）。具体目标2研究了通过蛋白酶体抑制作用自噬激活的病理生理学意义。这是为了测试蛋白酶体功能不全（PFI）激活心脏自噬的假设，而这种激活可以补偿由PFI引起的蛋白质质量控制障碍。特定的目标3检验了损害AM的假设损害了蛋白酶体底物的降解，并且UPS和自噬中的二人损伤通过RIP1-RIP3介导的途径触发了CM坏死。预计这项研究的完成将显着提高我们对蛋白质质量控制和心脏中蛋白质质量控制途径的理解，特别是通过CSN进行协调调节，这将有助于寻找新的策略，以预防和/或更有效地治疗CHF，这是美国主要的死亡和残疾原因。