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：
10311508
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/10311508
关键词：
Address Adult Affect Annexins Apoptosis Biological Models Branched-Chain Amino Acids Cardiac 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 induced pluripotent stem cell derived cardiomyocytes 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.

概括心脏病是美国男性和女性死亡率的主要原因。肥胖是快速增长的流行病和心肌病和心力衰竭发展的主要危险因素。与肥胖相关心肌病的病理学与脂肪异常积累和脂肪毒性代谢产物。防止这种脂肪毒性作用是治疗干预心脏的潜在途径疾病和心力衰竭。然而，心脏脂肪毒性的分子机制仍然难以捉摸。在此提案中，我们试图通过利用我们既定，稳健的神经酰胺和高脂 - diet（HFD）诱导的脂肪毒性心肌病（LCM）的果蝇心脏模型，该模型在哺乳动物LCM中观察到的表现出LCM样病理，包括受损的收缩力和升高两种饮食都会积聚甘油三酸酯脂肪和鞘脂神经酰胺。果蝇非常具有高度组成的代谢途径和心脏生理学的多功能遗传模型系统，非常适合地址LCM的基本机制。尽管如此，我们将在人类中验证果蝇中的发现源自诱导的多能干细胞（HIPSC-CM）的心肌细胞以获得进一步的人类相关洞悉LCM的机制（与共同研究员Alexandre Colas合作 - 见信）。在神经酰胺 - 蛋白质陷阱实验中，我们确定了3个富集的推定神经酰胺相互作用的本体论蛋白质（180个推定重叠的小鼠人类CIPS）：（1）肉瘤调节蛋白（40 CIPS），包括肌球蛋白伴侣不协调的45b（UNC45B），（2）代谢调节蛋白（33 CIPS），包括脂肪酸合酶FASN和（3）凋亡和DNA损伤反应（DDR）蛋白（21 CIPS）。确实，发现了这一点 Fly心脏中的心脏UNC45过表达或FASN RNAi敲低可防止神经酰胺诱导的LCM。 lcm- 诱导和亚阈值敏感的神经酰胺和高脂肪处理将用于询问上述 CIPS参加LCM。这将是详细确定神经酰胺的机制的第一步与这三类蛋白质相互作用，以及如何破坏或保护心脏功能和稳态。目的是构建和测试肌原纤维维护/脂肪形成/以凋亡为中心的调节网络加权新型CIP，我们将在LCM模型中对其进行进一步评估。