The COP9 SIgnalosome in the Heart

COP9 心脏中的信号体

• 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
• 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

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(申请人提供)：泛素-蛋白酶体系统(UPS)功能障碍和自噬是两种主要的细胞内蛋白分解途径，已在多种心脏疾病中观察到，并与充血性心力衰竭(CHF)的发生有关，充血性心力衰竭是几乎所有心脏疾病的最终共同途径，并困扰着数百万美国人的生活。COP9信号体(CSN)是一个进化保守的蛋白质复合体，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不仅是UPS介导的蛋白降解所必需的，也是自噬所必需的，以发挥其在小鼠心脏中的蛋白质质量控制作用。围产期心肌细胞限制性CSN亚基8基因敲除(CR-Csn8KO)主要导致完整小鼠心肌细胞(CM)大量坏死，在此之前自噬-溶酶体途径受损，并伴有UPS故障。CR-Csn8KO小鼠发展为扩张型心肌病并过早死于心力衰竭。基于这些令人兴奋的新发现，我们建议破译CSN8/CSN调节心脏自噬-溶酶体途径和心肌细胞生存的分子机制。利用创新的遗传操作和对完整小鼠的药理试验相结合，我们将追求三个特定的目标来测试中心假设，即CSN8/CSN通过Rab7促进AM并促进CMS中的PQC，从而通过抑制RIP1/RIP3介导的坏死途径提高CM的存活率。特定目的1定义了CSN8/CSN促进自噬的分子机制。这将检验CSN8/CSN通过Rab7调节自噬小体成熟(AM)的假设。特定目的2研究蛋白酶体抑制激活自噬的病理生理学意义。这是为了验证一种假设，即蛋白酶体功能不全(PFI)激活心脏自噬，这种激活可以补偿由PFI引起的蛋白质质量控制损害。特异性目标3验证了以下假设：AM受损会损害蛋白酶体底物的降解，UPS和自噬的双重损伤通过RIP1-RIP3介导的途径触发CM坏死。这项研究的完成预计将显著提高我们对心脏中蛋白质质量控制和降解途径如何协调调节的理解，特别是由CSN调节，这将促进寻找新的策略来预防和/或更有效地治疗CHF，CHF是美国死亡和残疾的主要原因。