Molecular Pathogenesis of Protein Surplus Cardiomyopathy

蛋白质过剩心肌病的分子发病机制

基本信息

批准号：
7822353
负责人：
XUEJUN WANG
金额：
$ 1.66万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822353
关键词：
Adult Amyloid Amyloidosis Animal Model Autophagocytosis Calcineurin Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cause of Death Cell Aggregation Cell physiology Clinical Management Congestive Heart Failure Desmin Diagnosis Disease Dominant-Negative Mutation Electrophysiology (science)Excision Failure Figs - dietary Filament Functional disorder Gene Expression Gene Mutation Genes Goals Healthcare Heart Heart Diseases Heart Hypertrophy Human Impairment Laboratories Left Life Light Measures Mediating Molecular Mus Muscle Cells Mutation Myopathy NFAT Pathway Pathogenesis Pathway interactions Peptide Hydrolases Perinatal Physiologic intraventricular pressure Play Production Proteins Proteolysis Quality Control Recovery Regulation Research Project Grants Role Signaling Protein Syndrome System Testing Transactivation Transgenic Organisms Ubiquitin constriction genetic manipulation heart function hypertensive heart disease insight mouse model multicatalytic endopeptidase complex pressure prevent protein aggregation public health relevance

项目摘要

DESCRIPTION (provided by applicant): The broad long term goal of the PI's laboratory is to help define the mechanisms underlying the progression of various heart diseases to congestive heart failure (CHF). In the present proposal animal models mimic human desmin-related cardiomyopathy (DRC) and hypertensive heart disease will be respectively investigated. Although DRC is not a common heart disease but understanding its pathogenesis will shed lights on many common forms of heart disease, especially those with increased production of abnormal proteins in cardiomyocytes. DRC is the cardiac component of desmin-related myopathy (DRM) which is often caused by genetic mutations. DRM or DRC is characterized by aberrant protein aggregation in muscle cells and this aggregation appears to play a central role in DRC pathogenesis. Notably, abnormal protein aggregation in the form of amyloid oligomers was also observed in human CHF resulting from common forms of heart disease. Intracellular protein aggregation and proteolytic disturbance are recently observed also in pressure overloaded mouse hearts. Hence, pathogenic insights gained from studying DRC may provide critical information for understanding molecular pathogenesis of CHF resulting from common cardiovascular disease. The ubiquitin- proteasome system (UPS) is responsible for the degradation of most cellular proteins and thereby plays indispensible roles in intracellular protein quality control and the regulation of virtually all cellular functions. In the previous project period, we have successfully unveiled severe proteasome (psm) impairment by abnormal protein aggregation in DRC mouse hearts. Notably, psm dysfunction is also observed in animal models of many other cardiac disorders, including pressure overload cardiomyopathy. It has also been implicated in human CHF of most causes. However, the pathophysiological significance of psm dysfunction in the heart is virtually unknown and will be extremely important to be defined. Accordingly, we propose to test an overall hypothesis that the inadequacy in psm-mediated proteolysis plays an essential role in DRC and in pressure overload cardiomyopathy, by pursuing the following 4 Specific Aims: (1) To determine the sufficiency of perinatal or adult onset cardiomyocyte-restricted psm inhibition (CR-PSMI) to induce cardiomyopathy and its reversibility in mice; (2) To investigate the impact of moderate and severe CR-PSMI on the removal of bona fide normal and abnormal proteins in the heart and investigate the functional relationship between psm- mediated proteolysis and autophagy in cardiomyocytes in mice; (3) To determine the necessity of psm functional insufficiency in the pathogenesis of DRC in mice; and (4) To determine the role of psm dysfunction in pressure overload cardiac remodeling and failure in mice. PUBLIC HEALTH RELEVANCE: Congestive heart failure is the final common pathway of virtually all heart disease and is the most expensive single diagnosis in US health care. It is a highly lethal and disabling syndrome. Despite recent advances in its clinical management, it remains the leading cause of death in the US. This research project will help deepen our understanding on the molecular mechanisms underlying the progression of various heart diseases to congestive heart failure, which will ultimately facilitate the search for new measures to prevent or more effectively treat this common and yet life-threatening disorder.

描述（由申请人提供）：PI实验室的广泛长期目标是帮助定义各种心脏病发展到充血性心力衰竭（CHF）的基础机制。在本提案中，动物模型将分别研究与人类脱敏相关的心肌病（DRC）和高血压心脏病。尽管DRC不是一种常见的心脏病，但了解其发病机理会散发出许多常见的心脏病形式，尤其是那些患心肌细胞异常蛋白质产生的人。 DRC是Desmin相关肌病（DRM）的心脏成分，通常是由基因突变引起的。 DRM或DRC的特征是肌肉细胞中异常的蛋白质聚集，该聚集似乎在DRC发病机理中起着核心作用。值得注意的是，在人CHF中还观察到以心脏病的常见形式引起的淀粉样蛋白低聚物形式的异常蛋白质聚集。最近在压力超负荷的小鼠心脏中，最近还观察到细胞内蛋白质聚集和蛋白水解障碍。因此，研究DRC从研究中获得的致病见解可能会提供关键信息，以了解常见心血管疾病导致CHF的分子发病机理。泛素蛋白酶体系统（UPS）负责大多数细胞蛋白的降解，从而在细胞内蛋白质质量控制中起着不可或缺的作用，并且几乎所有细胞功能的调节。在上一个项目期间，我们成功地揭示了DRC小鼠心脏中异常蛋白质聚集的严重蛋白酶体（PSM）损害。值得注意的是，在许多其他心脏病的动物模型（包括压力过负荷心肌病）中还观察到PSM功能障碍。它也与大多数原因的人类冠心有关。但是，PSM功能障碍在心脏中的病理生理意义实际上是未知的，并且要定义非常重要。 Accordingly, we propose to test an overall hypothesis that the inadequacy in psm-mediated proteolysis plays an essential role in DRC and in pressure overload cardiomyopathy, by pursuing the following 4 Specific Aims: (1) To determine the sufficiency of perinatal or adult onset cardiomyocyte-restricted psm inhibition (CR-PSMI) to induce cardiomyopathy and its reversibility in mice; （2）研究中度和严重的Cr-PSMI对心脏中真正的正常和异常蛋白质去除的影响，并研究小鼠心肌细胞中PSM介导的蛋白水解与自噬之间的功能关系；（3）确定小鼠DRC发病机理中PSM功能不足的必要性；（4）确定PSM功能障碍在压力过载心脏重塑和小鼠衰竭中的作用。公共卫生相关性：充血性心力衰竭是几乎所有心脏病的最终常见途径，也是美国医疗保健中最昂贵的单一诊断。这是一种高度致命和致命的综合症。尽管其临床管理最近取得了进步，但它仍然是美国死亡的主要原因。该研究项目将有助于加深我们对各种心脏病发展为充血性心力衰竭进展的分子机制的理解，这最终将促进寻找新的措施，以防止或更有效地治疗这种常见且威胁生命的疾病。