Metabolic underpinnings of AL amyloid cardiomyopathy

AL 淀粉样心肌病的代谢基础

基本信息

批准号：
9034665
负责人：
Ronglih Liao
金额：
$ 61.75万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9034665
关键词：
Acyl CoA Dehydrogenases Adult Amyloid Amyloid Fibrils Amyloidosis Animal Model Animals Applications Grants Basic Science Binding Binding Proteins Biological Markers Biology Biopsy Bypass Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular system Carnitine Cell model Cells Cessation of life Clinical Research Collection Cytochromes Deposition Development Diagnosis Diagnostic Diagnostic Imaging Disease Enzymes Functional disorder Health Heart Heart Diseases Human In Vitro International Laboratories Light Light-Chain Immunoglobulins Mass Spectrum Analysis Mediating Medium chain fatty acid Metabolic Mitochondria Modeling Pathogenesis Pathway interactions Patients Plasma Plasma Proteins Process Production Proteins Role Testing Therapeutic Translational Research Translations United States National Institutes of Health Unsaturated Fatty Acids Up-Regulation Work Zebrafish acyl-CoA dehydrogenase base circulating biomarkers citrate carrier cohort fatty acid metabolism immunoglobulin deposition disease in vivo insight lipid metabolism metabolomics mitochondrial dysfunction novel strategies oxidation primary amyloidosis of light chain type response

项目摘要

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.

描述（由申请人提供）：淀粉样轻链 (AL) 或原发性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 淀粉样变性患者出现心脏受累，导致发展为快速进展的 AL 淀粉样变性心肌病。对当前疗法的反应有限，中位生存期为 13 个月，我们已经确定心肌细胞对从 AL 淀粉样蛋白患者中分离出的人淀粉样蛋白轻链 (AL-LC) 具有强效心脏毒性反应。然而，AL-LC 引起心脏毒性的机制仍不清楚，我们最近发现 AL-LC 心脏毒性在线粒体上达到最高水平。 LC 选择性拮抗长链不饱和脂肪酸 (LCUFA) 的线粒体 β-氧化，并代偿性上调 β-氧化的 ER 途径， AL-LC 心脏毒性细胞模型和 AL 淀粉样蛋白心肌病患者中存在的  氧化副产物显着增加。在本提案中，我们将利用对 AL 淀粉样蛋白心肌病患者最大的队列研究、建立的细胞和动物模型。 AL-LC 心脏毒性的研究，以及基于最先进质谱的代谢组学 (1) 定义 AL 淀粉样心肌病的体内代谢特征并确定首次早期诊断该疾病的代谢生物标志物；(2) 确定线粒体 -氧化转移脂质代谢的功能意义 ER β-氧化以及该过程对 AL-LC 心脏毒性发病机制的贡献；(3) 确定使用批准的药物绕过或恢复线粒体 β-氧化是否可以预防 AL-LC 心肌病的发生。我们的项目以最近 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 [RO1]）为中心，将为这一疾病过程提供前所未有的机制、诊断和治疗见解。