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（由申请人提供）：泛素蛋白酶体系统（UPS）和自噬（两种主要的细胞内蛋白水解途径）的功能障碍已在多种心脏病中观察到，并与充血性心力衰竭（CHF）的发生有关，而充血性心力衰竭（CHF）是几乎所有心脏病的最终共同途径，困扰着数百万美国人的生活。 COP9 信号体 (CSN) 是一种进化上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不仅是UPS介导的蛋白水解所必需的，而且也是自噬所必需的，以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性 CSN 8 亚基敲除 (CR-Csn8KO) 主要导致完整小鼠出现大量心肌细胞 (CM) 坏死，在此之前会出现自噬溶酶体途径受损并伴有 UPS 故障。 CR-Csn8KO 小鼠出现扩张型心肌病并因 CHF 过早死亡。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存活的分子机制。通过在完整小鼠中结合创新的基因操作和药理学研究，我们将追求三个具体目标，以测试 Csn8/CSN 通过 Rab7 促进 AM 并促进 CM 中的 PQC 的中心假设，从而通过抑制 RIP1/RIP3 介导的坏死途径来促进 CM 存活。具体目标 1 定义了 Csn8/CSN 促进自噬的分子机制。这将检验 Csn8/CSN 通过 Rab7 调节自噬体成熟 (AM) 的假设。具体目标 2 研究蛋白酶体抑制激活自噬的病理生理学意义。这是为了检验蛋白酶体功能不全 (PFI) 激活心脏自噬并且这种激活补偿 PFI 引起的蛋白质质量控​​制损伤的假设。具体目标 3 测试了以下假设：AM 受损会损害蛋白酶体底物的降解，并且 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着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，特别是通过 CSN，这将有助于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。