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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.