The COP9 Signalosome in the Heart

COP9 心脏中的信号体

• 批准号: 7631261
• 负责人: XUEJUN WANG
• 金额: $ 35.78万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631261
• 关键词: Affect; American; Amyloid Proteins; Amyloidosis; Apoptotic; Attenuated; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Complex; Congenital Heart Defects; Congestive Heart Failure; Data; Degradation Pathway; Desmin; Deubiquitination; Development; Down-Regulation; Eukaryota; Functional disorder; Gene Targeting; Gene Transfer Techniques; Genes; Goals; Health; Heart; Heart Diseases; Hematopoiesis; Homeostasis; Human; Knock-out; Laboratories; Life; Link; Lower Organism; Malignant Neoplasms; Mammalian Cell; Mammals; Measures; Mediating; Molecular; Molecular Biology; Mouse Strains; Mus; Neonatal; Organ; Pathogenesis; Pathway interactions; Physiological; Play; Protein Subunits; Proteins; Proteolysis; Quality Control; Regulation; Reporting; Research; Research Personnel; Role; Staging; Structure; Survival Analysis; Syndrome; System; Testing; Therapeutic; Touch sensation; Ubiquitin; Ubiquitination; base; genetic regulatory protein; human disease; insight; knockout gene; loss of function; multicatalytic endopeptidase complex; mutant; novel therapeutics; overexpression; postnatal; prevent; protein aggregation; protein complex; protein degradation; protein misfolding; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The ubiquitin proteasome system (UPS) is responsible for the degradation of most proteins in the cell. By clearing abnormal proteins and removing normal proteins that are no longer needed, UPS-mediated proteolysis plays an extremely important role in both quality control of the cell and regulation of the intracellular homeostasis, thereby touching virtually every corner of the cell. Recent studies have revealed that UPS proteolytic function in the heart can be severely impaired by abnormal protein aggregation which is often observed in failing human hearts, suggesting that UPS dysfunction may play an extremely important role in the progression of congestive heart failure (CHF), a clinical syndrome that affects the health and life of millions of Americans. Therefore, a potential new therapeutic strategy is to normalize UPS function in the heart with CHF. In order to do so, the mechanisms that regulate UPS function must first be elucidated. A long term goal of this proposal is to delineate the molecular mechanisms that regulate protein turnover in mammalian hearts by the UPS and provide molecular biology basis for harnessing UPS proteolytic function to treat CHF. A recently discovered protein complex, the COP9 signalosome (CSN) consisting of 8 unique protein subunits (CSN1 approximately CSN8), is evolutionary conserved throughout the eukaryotes. Studies from lower organisms and cultured mammalian cells have shown that CSN plays important roles in many basic cellular processes including regulating the activity of the UPS. This study will test a central hypothesis that CSN cooperates with cullin-based ubiquitin E3 ligases in destruction of regulatory proteins while it suppresses the degradation of abnormal proteins by the proteasome; therefore, it is required for heart muscle cell survival, postnatal cardiac development, and cardiac function. Through conditional gene targeting, a CSN hypomorphic mouse strain has been generated and the heart muscle cells restricted knockout of a CSN gene at the neonatal stage has also been achieved. The impact of CSN loss-of-function or reduced function in the heart on cardiac structure and function and its modulation of the UPS function in the heart will then be defined. This will provide important insights into the function of CSN in the heart and CSN-dependent regulation of UPS functions in the heart. Ultimately, this will help search for new measures to prevent and/or more effectively treat human CHF.

描述（由申请人提供）：泛素蛋白酶体系统（UPS）负责细胞中大多数蛋白质的降解。通过清除异常蛋白质并去除不再需要的正常蛋白质，UPS介导的蛋白水解在细胞质量控制和细胞内稳态调节中发挥着极其重要的作用，从而几乎触及细胞的每个角落。最近的研究表明，心脏中的 UPS 蛋白水解功能可能会因异常蛋白质聚集而严重受损，这在衰竭的人类心脏中经常观察到，这表明 UPS 功能障碍可能在充血性心力衰竭 (CHF) 的进展中发挥极其重要的作用，充血性心力衰竭 (CHF) 是一种影响数百万美国人健康和生活的临床综合征。因此，一种潜在的新治疗策略是使 CHF 患者的心脏 UPS 功能正常化。为此，必须首先阐明调节 UPS 功能的机制。该提案的长期目标是阐明 UPS 调节哺乳动物心脏中蛋白质周转的分子机制，并为利用 UPS 蛋白水解功能治疗 CHF​​ 提供分子生物学基础。最近发现的蛋白质复合物，COP9 信号体 (CSN) 由 8 个独特的蛋白质亚基（CSN1 大约 CSN8）组成，在整个真核生物中是进化保守的。对低等生物和培养的哺乳动物细胞的研究表明，CSN 在许多基本细胞过程中发挥着重要作用，包括调节 UPS 的活性。这项研究将检验一个中心假设，即 CSN 与基于 cullin 的泛素 E3 连接酶合作破坏调节蛋白，同时抑制蛋白酶体对异常蛋白的降解；因此，它是心肌细胞存活、出生后心脏发育和心脏功能所必需的。通过条件基因打靶，产生了CSN亚型小鼠品系，并实现了新生儿阶段心肌细胞CSN基因的限制性敲除。然后将定义心脏中 CSN 功能丧失或功能降低对心脏结构和功能的影响及其对心脏 UPS 功能的调节。这将为了解心脏中 CSN 的功能以及心脏中 UPS 功能的 CSN 依赖性调节提供重要见解。最终，这将有助于寻找新的措施来预防和/或更有效地治疗人类慢性心力衰竭。