Molecular Mechanisms and Treatment of Primary Amyloid (AL) Cardiomyopathy

描述（由申请人提供）：原发性淀粉样变性（AL）是美国最常见的系统性淀粉样变性，是一种浆细胞恶液质，导致免疫球蛋白轻链蛋白的克隆产生和随后的多器官淀粉样纤维沉积，心脏和肾脏（单独或一起）是最常累及的器官。心脏受累伴充血性心力衰竭是原发性淀粉样变性最常见的死亡原因，这是由于发生了快速进展的心肌病，预后不良，通常在数月内发生。虽然这种疾病在几十年前就被发现了，但原发性淀粉样心肌病的分子机制仍然未知。我们最近提供了第一个洞察原发性淀粉样心肌病的病理生理学，挑战现有的假设-心功能不全是继发于心肌的淀粉样纤维的物理浸润，并首次证明，人淀粉样轻链蛋白对心肌细胞功能的直接影响独立于淀粉样纤维的形成。此外，我们的数据表明，淀粉样轻链蛋白诱导的心肌细胞功能障碍是通过激活特定的细胞信号通路和产生活性氧。这些发现提供了对原发性淀粉样心肌病的第一个机制性见解，并导致了我们的中心假设的产生，即循环免疫球蛋白轻链直接导致心肌细胞功能障碍，并通过激活氧化还原敏感性和应激激活激酶信号级联，促进原发性淀粉样心肌病的快速进展，独立于间质纤维沉积，以及随后的细胞氧化应激。利用细胞生物学、心肌细胞生理学和遗传学的多学科方法，以及体外和体内方法，本提案的主要目标是扩展我们以前的发现，并具体确定：（1）原发性淀粉样心肌病的分子机制（具体目标1和2）和（2）治疗原发性淀粉样心肌病的潜在治疗靶点（具体目标3）。从这个建议中获得的结果，我们希望有助于我们对AL心肌病的理解，从而利用治疗潜力治愈这种快速致命的疾病。

DESCRIPTION (provided by applicant): Primary amyloidosis (AL), the most common systemic amyloidosis in the US, is a plasma cell dyscrasia resulting in the clonal production of immunoglobulin light chain proteins and subsequent amyloid fibril deposition in multi-organ, The heart and the kidney, alone or together, are the most frequently involved organs. Cardiac involvement with congestive heart failure is the most frequent cause of death in primary amyloidosis, due to the development of a rapidly progressive cardiomyopathy, with ill prognosis, usually within months. While this disease has been identified decades ago, yet, the molecular mechanisms underlying primary amyloid cardiomyopathy remain unknown. We have recently provided the first insights into the pathophysiology of primary amyloid cardiomyopathy, challenging existing hypotheses - that cardiac dysfunction is secondary to physical infiltration of the myocardium by amyloid fibrils and demonstrating, for the first time, a direct effect of human amyloidogenic light chain proteins on cardiomyocyte function independent of amyloid fibril formation. Furthermore, our data suggest that amyloid light chain proteins induced cardiomyocyte dysfunction is through activation of specific cellular signaling pathways and generation of reactive oxygen species. These findings have provided the first mechanistic insight into primary amyloid cardiomyopathy, and have led to the generation of our central hypothesis that circulating immunoglobulin light chains directly result in cardiomyocyte dysfunction and contribute to the rapid progression of primary amyloid cardiomyopathy, independent of interstitial fibril deposition, through activation of redox-sensitive and stress-activated kinases signaling cascades, and subsequent cellular oxidant stress. Utilizing a multidisciplinary approach of cellular biology, cardiomyocyte physiology, and genetics, as well as in-vitro and in-vivo methodologies, the major goal of this proposal is to expand upon our previous findings and to determine specifically: (1) the molecular mechanisms underlying primary amyloid cardiomyopathy (Specific Aims 1 & 2) and (2) potential therapeutic targets for the treatment of primary amyloid cardiomyopathy (Specific Aim 3). The results obtained from this proposal, we hope to contribute to our understanding of AL cardiomyopathy, and thus, harness the therapeutic potential to cure this rapidly fatal disease.