The COP9 Signalosome in the Heart

COP9 心脏中的信号体

基本信息

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
项目类别：
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

项目摘要

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的质量控制和细胞内稳态的调节中都起着极为重要的作用，从而几乎接触细胞的每个角落。最近的研究表明，异常蛋白质聚集在心脏中的UPS蛋白水解功能会严重损害，这在人类心脏失败中经常被观察到，这表明UPS功能障碍可能在充血性心力衰竭（CHF）（CHF）的发展中起着极为重要的作用，这是一种影响了数以百万计的美国人的健康和生命的临床综合征。因此，潜在的新治疗策略是用CHF在心脏中的UPS功能正常化。为此，必须首先阐明调节UPS功能的机制。该建议的长期目标是描述UPS调节哺乳动物心脏中蛋白质更换的分子机制，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，即由8个独特的蛋白亚基（CSN1大约CSN8）组成的COP9信号体（CSN），是整个真核生物的进化保守的。来自较低生物体和培养的哺乳动物细胞的研究表明，CSN在许多基本的细胞过程中起着重要作用，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连接酶合作在调节蛋白的破坏中，同时抑制了蛋白酶体对异常蛋白的降解。因此，这是心肌细胞存活，产后心脏发育和心脏功能所必需的。通过有条件的基因靶向，已经产生了CSN肌电小鼠菌株，并且还达到了新生儿阶段中CSN基因的敲除敲除。然后将定义CSN功能丧失或功能降低功能对心脏结构和功能的影响以及其对心脏中UPS功能的调节的影响。这将为CSN在心脏中的功能和CSN依赖性调节中的UPS功能中的功能提供重要的见解。最终，这将有助于寻找新的措施，以预防和/或更有效地治疗人类CHF。