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寡聚体（PAO）在人类心力衰竭中可能发挥的作用。我们注意到，来自患病心脏的心肌细胞含有一种蛋白质，该蛋白质与能够检测毒性蛋白PAO的抗体反应，PAO通常与基于淀粉样蛋白的神经退行性疾病相关。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，1B晶体蛋白突变小鼠，也积累PAO的心肌细胞，是一个独特的有用的和相关的系统，模型迄今研究不足的现象，积累PAO的心肌细胞中的成人和小儿心力衰竭患者。因此，我们的目标是了解导致PAO蓄积的致病途径，确定其在心肌细胞中的毒性，并确定因CryABR120G表达而发生的扩张型心肌病和心力衰竭的潜在治疗靶点或方式。目的1将检验PAO的心肌细胞蓄积在人心力衰竭人群中广泛存在的假设，包括年龄组和疾病类型。目的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）表达来测试PAO介导的心力衰竭可以逆转的假设。目的3将在CryABR120G心肌病心脏中表达抗凋亡因子，以确定在持续CryABR120G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心脏中发生了心肌细胞凋亡，但程序性细胞死亡是该模型中使心脏向衰竭转变的主要病因的外围和附带因素。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，并确定新的靶点，用于干扰在广泛的心血管疾病中发生的过程。我们发现心脏含有一种通常与神经退行性疾病有关的蛋白质。这种有毒蛋白质只存在于患病的心脏中，我们的实验将确切地研究这种蛋白质在何时何地积累以及如何导致心血管疾病。

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.