Metabolic underpinnings of AL amyloid cardiomyopathy

 描述(申请人提供)：淀粉样轻链(AL)或原发淀粉样变性是全世界最常见的系统性淀粉样变性。超过一半的AL淀粉样变性患者存在心脏受累，导致快速进展的AL淀粉样心肌病，对目前的治疗反应有限，中位生存期为13个月。我们已经发现，从AL淀粉样心肌病患者中分离出的人淀粉样变轻链(AL-LC)对心肌细胞产生了强烈的心脏毒性反应，这是该疾病发病机制的关键组成部分。然而，AL-LC所致心脏毒性的机制尚不清楚。我们最近发现，AL-LC的心脏毒性最终发生在线粒体上。利用综合代谢组学方法，我们发现AL-LC选择性地拮抗线粒体氧化长链不饱和脂肪酸，并代偿上调ER途径的-氧化，在AL-LC心脏毒性细胞模型和AL淀粉样心肌病患者中存在的-氧化副产物显著增加。在这项建议中，我们将利用对AL淀粉样心肌病患者的最大聚集队列的研究，建立AL-LC心脏毒性的细胞和动物模型，以及基于最先进的基于质谱学的代谢组学来(1)确定AL淀粉样心肌病的体内代谢物特征，并确定该疾病的第一个早期诊断代谢物生物标志物；(2)确定从线粒体氧化转移脂代谢的功能意义 (3)确定使用已批准的药物绕过或恢复线粒体-氧化是否有助于预防AL-淀粉样心肌病的发展。我们的项目集中于NIH最近的PA公告(PA-13-286：系统性淀粉样变性：基础、翻译和临床研究[RO1])，并将对这一疾病过程提供前所未有的机制、诊断和治疗洞察力。

 DESCRIPTION (provided by applicant): Amyloid light chain (AL) or primary amyloidosis is the most prevalent systemic amyloidosis worldwide. More than half of patients with AL amyloidosis present with cardiac involvement, resulting in the development of a rapidly progressive AL amyloid cardiomyopathy, with limited response to current therapies and median survival of 13 months. We have identified a potent cardiotoxic response in cardiomyocytes to human amyloidogenic light chain (AL-LC) isolated from patients with AL amyloid cardiomyopathy, as a critical component of the disease's pathogenesis. However, the mechanism underlying AL-LC induced cardiotoxicity have remained unclear. We have recently found that AL-LC cardiotoxicity culminates on the mitochondrial. Using comprehensive metabolomics approaches, we have found that AL-LC results in selective antagonism of mitochondrial -oxidation of long chain unsaturated fatty acids (LCUFA) with compensatory upregulation of an ER pathway of -oxidation, with marked increase in byproducts of -oxidation present in cellular models of AL-LC cardiotoxicity and patients with AL amyloid cardiomyopathy. In this proposal, we will leverage study of the largest amassed cohort of patients with AL amyloid cardiomyopathy, established cellular and animal models of AL-LC cardiotoxicity, and state of the art mass spectrometry based metabolomics to (1) define the in vivo metabolite signature of AL amyloid cardiomyopathy and to identify a first early diagnostic metabolite biomarker for this disease; (2) determine the functional significance of shifting lipid metabolism from mitochondrial -oxidation to ER -oxidation and the contribution of this process to the pathogenesis of AL-LC cardiotoxicity; and (3) to determine if bypassing or restoring mitochondrial -oxidation using approved agents may serve to protect against the development of AL amyloid cardiomyopathy. Our project is centered in line with the recent NIH's PA announcement (PA-13-286: Systemic Amyloidosis: Basic, Translational and Clinical Research [RO1]) and will provide unprecedented mechanistic, diagnostic and therapeutic insight into this disease process.