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Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicine

精准医学揭示家族性扩张型心肌病发病机制

基本信息

批准号：
10586652
负责人：
Ioannis Karakikes
金额：
$ 51.66万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586652
关键词：
ATF2 gene BAG3 gene Binding Biological Assay CRISPR/Cas technology Carbon Cardiac Cardiac Myocytes Caring Cellular Stress Cessation of life Complex Coupled Data Dependovirus Development Dilatation - action Dilated Cardiomyopathy Disease Echocardiography Functional disorder Gene Delivery Gene Expression Gene Transduction Agent Genes Genetic Genetic Heterogeneity Genetic Predisposition to Disease Genetic Transcription Goals Heart Heart Diseases Heart failure Human In Vitro Individual Knock-in Knock-in Mouse Mediating Metabolism Modeling Molecular Target Mus Muscle function Mutation Myocardium Ontology PF4 Gene Pathogenesis Pathologic Pathway interactions Patients Phenocopy Phenotype Physiology Population Prevalence Privatization Proteins Publishing Regulation Research Role Safety Sarcomeres Sarcoplasmic Reticulum Signal Transduction Stress Structure Testing Therapeutic Therapeutic Intervention Translating Up-Regulation Work activating transcription factor 4 biological adaptation to stress cardioprotection chromatin immunoprecipitation clinically relevant cohort effective therapy familial dilated cardiomyopathy functional genomics gene therapy heart function high throughput screening improved in vivo in vivo Model induced pluripotent stem cell interdisciplinary approach molecular phenotype mouse model new therapeutic target novel overexpression precision medicine promoter protein expression response targeted treatment therapeutic candidate therapeutic target transcription factor treatment strategy

项目摘要

Summary Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. Despite the progress in unraveling the genetic basis of DCM, there is a lack of disease-modifying therapies that target the underlying genetic etiology. In preliminary studies, we identified the transcription factor 4 (ATF4) as a potential target for therapeutic interventions in genetic DCM. ATF4 is a critical factor mediating the integrated stress response; an adaptive pathway activated in response to stress. ATF4 is selectively translated in response to specific forms of cellular stress to induce the expression of genes involved in adaptation to stress. Here we propose a multidisciplinary approach to explore the potential role of ATF4-mediated regulation of one-carbon metabolism in cardiac physiology and develop novel mutation-agnostic gene therapy for DCM. In Aim 1, we will test whether ATF4 overexpression can rescue the contractility deficit, a hallmark of DCM, in a mutation-agnostic manner using iPSC-CMs derived for patients carrying DCM-causing mutation in diverse gene ontologies. In Aim 2, we will examine the potential role of ATF4-mediated regulation of one-carbon metabolism gene expression in cardiomyocyte function. In Aim 3, we will use AAV-mediated overexpression of ATF4 in vivo and test whether ATF4 signaling could reverse or halt the progression of DCM in vivo. Unlike conventional gene therapies, our approach does not replace a faulty or missing gene. Instead, our approach aims at triggering a cardioprotective effect by bolstering the ATF4-dependent one-carbon metabolism gene expression in the heart. We hope to provide proof-of-concept for a new clinically relevant therapeutic strategy, paving the way for mutation-agnostic treatments for genetic DCM. Such treatments are likely to apply to other types of cardiac diseases such as heart failure.

总结