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Genetic Pathways in Ceramide-Associated Lipotoxic Cardiomyopathy and Heart Failure

神经酰胺相关脂毒性心肌病和心力衰竭的遗传途径

基本信息

批准号：
10065521
负责人：
ROLF BODMER
金额：
$ 48.75万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-10 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065521
关键词：
Address Adult Affect Annexins Apoptosis Biological Models Branched-Chain Amino Acids Cardiac Cardiac Myocytes Cardiac Myosins Cardiomyopathies Cardiovascular Diseases Cardiovascular system Categories Cell Death Cell Survival Cell physiology Ceramides Clinical Collaborations DNA Damage Data Development Diabetes Mellitus Diet Drosophila genus Epidemic Exhibits FASN gene Fatty acid glycerol esters Fatty-acid synthase Functional disorder Genetic Genetic Models Glycolysis Goals Grant Heart Heart Abnormalities Heart Diseases Heart failure Heat shock proteins High Fat Diet Homeostasis Human Knowledge Letters Lipids Maintenance Malignant Neoplasms Mammalian Genetics Mediating Mediator of activation protein Metabolic Metabolic Control Metabolic Pathway Modeling Molecular Molecular Chaperones Mus Muscle Myosin ATPase Obesity Ontology Pathologic Pathology Pathway interactions Physiology Prevention Proteins RNA Interference Regulation Research Research Personnel Risk Factors Role Sarcomeres Sphingolipids Structure Testing Therapeutic Intervention Triglycerides United States Woman cardioprotection cofactor dietary experimental study fatty acid metabolism fly genetic regulatory protein heart function in vivo induced pluripotent stem cell insight knock-down lipid biosynthesis men mortality novel overexpression overweight adults prevent response

项目摘要

Summary Heart disease is the leading cause of mortality in the United States in both men and women. Obesity is rapidly growing epidemic and a major risk factor for the development of cardiomyopathies and heart failure. The pathology of obesity-related cardiomyopathies is associated with abnormal cardiac accumulation of fat and lipotoxic metabolites. Preventing such lipotoxic effects is a potential avenue for therapeutic intervention in heart disease and heart failure. However, the molecular mechanisms of cardiac lipotoxicity remain elusive. In this proposal, we seek to address these gaps in knowledge by leveraging our established, robust Drosophila heart models of ceramide- and high-fat-diet (HFD)-induced lipotoxic cardiomyopathy (LCM), which exhibit LCM-like pathology observed in mammalian LCM, including compromised contractility and elevated accumulation of both triglyceride fat and sphingolipid ceramide with either diet. Drosophila is an extremely versatile genetic model system with highly conserved metabolic pathways and cardiac physiology, well suited to address fundamental mechanisms of LCM. Nevertheless, we will validate our findings in Drosophila in human cardiomyocytes that are derived from induced pluripotent stem cell (hiPSC-CMs) to gain further human relevant insights into the mechanisms of LCM (in collaboration with co-Investigator Dr. Alexandre Colas – see letter). In ceramide-protein trap experiments we identified 3 enriched ontologies of putative ceramide interacting proteins (180 putative overlapping mouse-human CIPs): (1) sarcomeric regulatory proteins (40 CIPs), including the myosin chaperone Uncoordinated-45b (Unc45b), (2) metabolic regulatory proteins (33 CIPs), including fatty acid synthase FASN, and (3) apoptosis & DNA damage response (DDR) proteins (21 CIPs). Indeed, found that cardiac Unc45 overexpression or FASN RNAi knockdown in the fly heart prevents ceramide-induced LCM. LCM- inducing and subthreshold-sensitizing ceramide and high fat treatments will be used to interrogate the above CIPs in participating in LCM. This will be the first step in determining in detail the mechanisms how ceramide interacts with these 3 classes of proteins and how that disrupts or protects cardiac function and homeostasis. The goal is to construct and test a myofibrillar maintenance/lipogenesis/ apoptosis-centric regulatory network weighted with novel CIPs, which we will experimentally evaluate further in our LCM models.

总结