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（由适用提供）：淀粉样轻链（AL）或原发性淀粉样变性是全球最普遍的全身性淀粉样变性。超过一半的AL淀粉样变性患者患有心脏受累，导致迅速进行性AL淀粉样蛋白心肌病的发展，对当前疗法的反应有限，中位生存期为13个月。我们已经确定了心肌细胞对从AL淀粉样蛋白心肌病患者分离的人淀粉样蛋白生成轻链（AL-LC）的潜在心脏毒性反应，这是该疾病发病机理的关键成分。但是，LC诱导的心脏毒性的基础机制尚不清楚。我们最近发现，al-LC心脏毒性在线粒体上达到顶点。使用全面的代谢组学方法，我们发现al-LC会导致长链不饱和脂肪酸（LCUFA）的线粒体选择性拮抗作用，并具有补偿性上调氧化的ER途径，并在细胞氧化症中显着增加了Allox cardiox cardiox cardiox cardiox cardiox cardiox cardiox cardiox cardyy cardyy cardyy cardyy cardyy cardyy cardyy cardyy cardyy的途径。心肌病。在这一提议中，我们将利用对Al淀粉样心脏疗法的最大积累同类群体的研究，建立的Al-LC心脏毒性的细胞和动物模型，以及基于ART群体的基于ART群体的代谢组学的状态，以（1）定义了体内的氧化膜型疾病，以识别该氧化甲状腺菌的疾病，以识别该疾病的初期诊断，以识别该疾病的早期诊断。（2）确定从线粒体氧化转移脂质代谢的功能意义 ER氧化和该过程对Al-LC心脏毒性发病机理的贡献；（3）确定使用批准的剂是否绕过或恢复线粒体氧化可能有助于防止Al淀粉样蛋白心肌病的发展。我们的项目以最近的NIH PA公告（PA-13-286：全身性淀粉样变性：基本，转化和临床研究[RO1]）为中心，并将为这种疾病过程提供前所未有的机械，诊断和治疗性的见解。