Cardiomyocyte Toxicity and Heart Failure in Desmin Related Cardiomyopathy

描述（由申请人提供）：本申请的长期目标是了解前淀粉样蛋白低聚物（PAO）在人类心力衰竭中的作用。我们注意到，来自患病心脏的心肌细胞含有一种蛋白质，该蛋白质对能够检测有毒蛋白质PAO的抗体起反应，PAO通常与淀粉样蛋白为基础的神经退行性疾病有关。随后，我们发现PAO存在于来自有限数量的不同病因的人类心力衰竭患者的心肌细胞中，这意味着它可能是心血管疾病的重要介质。我们认为，同样在心肌细胞中积累PAO的1B结晶蛋白突变小鼠，是一个独特而有用的相关系统，可以模拟迄今为止尚未研究的现象，即成人和儿童心力衰竭患者心肌细胞中PAO的积累。因此，目标是了解导致PAO积累的致病途径，确定其在心肌细胞中的毒性，并确定由于CryABR120G表达而导致的扩张性心肌病和心力衰竭的潜在治疗靶点或模式。目的1将验证PAO心肌细胞积累在人类心力衰竭人群中广泛存在的假设，不分年龄组和疾病类型。Aim 2将使用可诱导的心肌细胞特异性CryABR120G（一种导致人类肌肉疾病的突变蛋白）的表达来验证pao介导的心力衰竭可以逆转的假设。Aim 3将在CryABR120G心肌病心脏中表达抗凋亡因子，以确定在CryABR120G持续表达的情况下，预防程序性细胞死亡是否可以预防心力衰竭甚至逆转现有疾病。我们假设，尽管在CryABR120G心脏中发生心肌细胞凋亡，但程序性细胞死亡是外周性的，是该模型中导致心脏衰竭的主要病因。这些研究有可能在神经退行性疾病和心血管疾病之间建立广泛的联系，并确定干扰广泛心血管疾病过程的新靶点。我们发现心脏中含有一种蛋白质，这种蛋白质通常与神经退行性疾病有关。这种有毒蛋白质只在患病的心脏中发现，我们的实验将精确地检查这种蛋白质在何时何地积累，以及它是如何导致心血管疾病的。

DESCRIPTION (provided by applicant): The long term objective of this application is to understand the roles that pre-amyloid oligomers (PAO) may play in human heart failure. We noted that cardiomyocytes from diseased hearts contain a protein that reacts to antibodies able to detect a toxic protein(s), PAO, which is normally associated with the amyloid-based neurodegenerative diseases. Subsequently, we found that PAO is present in cardiomyocytes derived from a limited number of human heart failure patients of different etiologies, implying that it may be an important mediator of cardiovascular disease. We think that the 1B crystallin mutant mouse, which also accumulates PAO in the cardiomyocytes, is a uniquely useful and relevant system that models a heretofore understudied phenomenon, accumulation of PAO in the cardiomyocytes of both adult and pediatric heart failure patients. The goals, therefore, are to understand the pathogenic pathway that results in PAO accumulation, determine its toxicity in cardiomyocytes and define potential therapeutic targets or modalities for the resultant dilated cardiomyopathy and heart failure that occurs as a result of CryABR120G expression. Aim 1 will test the hypothesis that cardiomyocyte accumulation of PAO is widespread in the human heart failure population, across age groups and disease types. Aim 2 will use inducible, cardiomyocyte-specific CryABR120G (a mutant protein causative for human muscle disease), expression to test the hypothesis that PAO-mediated heart failure can be reversed. Aim 3 will express anti-apoptotic factors in CryABR120G cardiomyopathic hearts to determine if prevention of programmed cell death can, in the face of continuous CryABR120G expression, prevent heart failure or even reverse existing disease. We hypothesize that despite the occurrence of cardiomyocyte apoptosis in CryABR120G hearts, programmed cell death is peripheral and collateral to the primary etiology that transits the hearts toward failure in this model. These studies have the potential of establishing broad linkages between the neurodegenerative and cardiovascular diseases and identifying new targets for interfering with processes that occur in a broad range of cardiovascular disease. We have found that the heart contains a protein that is normally associated with neurodegenerative diseases. This toxic protein is only found in diseased hearts and our experiments will examine exactly when and where the protein accumulates and how it causes cardiovascular disease.