Metabolic underpinnings of AL amyloid cardiomyopathy

 描述（由申请方提供）：淀粉样轻链（AL）或原发性淀粉样变性是全球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，导致发展为快速进展的AL淀粉样心肌病，对当前治疗的反应有限，中位生存期为13个月。我们已经确定了一个强大的心脏毒性反应的心肌细胞，以人类淀粉样蛋白轻链（AL-LC）从AL淀粉样心肌病患者分离，作为疾病的发病机制的关键组成部分。然而，AL-LC诱导的心脏毒性的潜在机制仍不清楚。我们最近发现AL-LC心脏毒性在线粒体上达到高潮。使用综合代谢组学方法，我们已经发现AL-LC导致长链不饱和脂肪酸（LCUFA）的线粒体β-氧化的选择性拮抗作用，伴随β-氧化的ER途径的补偿性上调，在AL-LC心脏毒性的细胞模型和患有AL淀粉样心肌病的患者中存在的β-氧化的副产物显著增加。在该提案中，我们将利用对最大的AL淀粉样心肌病患者聚集队列的研究、建立的AL-LC心脏毒性的细胞和动物模型以及最先进的基于质谱的代谢组学来（1）定义AL淀粉样心肌病的体内代谢物特征并鉴定该疾病的第一个早期诊断代谢物生物标志物;（2）确定脂质代谢从线粒体β-氧化转移的功能意义 ER β-氧化以及该过程对AL-LC心脏毒性发病机制的贡献;和（3）确定使用批准的药剂旁路或恢复线粒体β-氧化是否可用于防止AL淀粉样心肌病的发展。我们的项目与最近NIH的PA公告（PA-13-286：系统性淀粉样变性：基础，转化和临床研究[RO 1]）一致，并将为这种疾病过程提供前所未有的机制，诊断和治疗见解。

 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.