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Molecular Mechanisms of Dystrophic Cardiomyopathy

营养不良性心肌病的分子机制

基本信息

批准号：
10402873
负责人：
Da-Zhi Wang
金额：
$ 50.32万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402873
关键词：
Affect Biological Assay CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cause of Death Communities DNA Sequence Alteration Development Dilated Cardiomyopathy Dimensions Disease Disease model Duchenne muscular dystrophy Dystrophin Exhibits Genes Genetic Genetic Diseases Goals Heart Heart Hypertrophy Heart failure Homeostasis Human In Vitro Knock-out Knockout Mice Knowledge Lead Link Mechanics Mediating Modeling Molecular Mus Muscle Muscle Weakness Mutant Strains Mice Mutate Mutation Myocardial dysfunction Myocardium Nature Oxidative Stress Oxidative Stress Pathway Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phenotype Play Preventive Process Proteins Role Signal Pathway Skeletal Muscle Stress Structure Systolic heart failure Technology Testing Therapeutic Thick Transgenic Organisms Utrophin cardiogenesis design disability dystrophic cardiomyopathy gene therapy genome editing genome-wide human disease induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes insight mdx mouse mouse model new therapeutic target novel novel therapeutic intervention overexpression response therapeutic evaluation therapeutically effective transcriptome wasting

项目摘要

MOLECULAR MECHANISMS OF DYSTROPHIC CARDIOMYOPATHY Abstract Cardiovascular diseases continue to be a leading cause of death and disability in USA. Duchenne Muscular Dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin gene that affects the structure and function of both cardiac and skeletal muscles. Heart failure has become a leading cause of fatalities in DMD patients. Our goal is to understand the molecular mechanisms underlying dystrophic cardiomyopathy, and to develop novel therapeutic strategies to treat this disease. We have first discovered CIP as a novel cardiomyocyte-enriched protein and we showed CIP is dynamically regulated in hypertrophic and dilated hearts. CIP physically interacts with dystrophin, mutation of which causes DMD. Importantly, we observed that CIP overexpression protects DMD mice (Mdx) from cardiomyopathy. These exciting findings have identified CIP as a novel component of the dystrophic cardiomyopathy pathway. In this study, we will define the molecular nature of CIP action and test the therapeutic potential of this protein in protecting the heart from developing dystrophic cardiomyopathy. More specifically, we will: 1) define the functional mechanism of CIP in dystrophic cardiomyopathy and heart failure; 2) test the therapeutic potential of CIP in dystrophic cardiomyopathy; 3) test the hypothesis that CIP mediates the oxidative stress signaling pathway in dystrophic cardiomyopathy. Studies proposed in this application will yield new insights into the pathogenesis of cardiomyopathy in DMD. Furthermore, we will demonstrate that therapy is a viable strategy to treat dystrophic cardiomyopathy in both murine and human disease models.

营养不良性心肌病的分子机制摘要心血管疾病仍然是美国死亡和残疾的主要原因。杜氏肌肌营养不良症（DMD）是由肌营养不良蛋白基因突变引起的遗传性疾病，其影响肌营养不良蛋白基因的结构和功能。心脏和骨骼肌的功能。心力衰竭已成为DMD死亡的主要原因患者我们的目标是了解营养不良性心肌病的分子机制，开发新的治疗策略来治疗这种疾病。我们首次发现CIP是一种新的心肌细胞富集蛋白，调节肥大和扩张的心脏。CIP与抗肌萎缩蛋白发生物理相互作用， DMD重要的是，我们观察到CIP过表达保护DMD小鼠（Mdx）免受心肌病。这些令人兴奋的发现已经将CIP鉴定为营养不良性心肌病途径的新组分。在这在这项研究中，我们将定义CIP作用的分子本质，并测试这种蛋白质在治疗中的潜力。保护心脏免于发展为营养不良性心肌病。具体而言，我们将： 1)明确CIP在营养不良性心肌病和心力衰竭中的作用机制; 2)测试CIP在营养不良性心肌病中的治疗潜力; 3)检验CIP介导营养不良性心肌病中氧化应激信号通路的假设。本申请中提出的研究将对DMD心肌病的发病机制产生新的见解。此外，我们将证明，治疗是一个可行的战略，以治疗营养不良性心肌病，在这两个鼠和人疾病模型。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiac ISL1-Interacting Protein, a Cardioprotective Factor, Inhibits the Transition From Cardiac Hypertrophy to Heart Failure.

心脏 ISL1 相互作用蛋白是一种心脏保护因子，可抑制心脏肥大向心力衰竭的转变

DOI：
10.3389/fcvm.2022.857049
发表时间：
2022
期刊：
Frontiers in cardiovascular medicine
影响因子：
3.6
作者：
Yan Y;Long T;Su Q;Wang Y;Chen K;Yang T;Zhao G;Ma Q;Hu X;Liu C;Liao X;Min W;Li S;Zhang D;Yang Y;Pu WT;Dong Y;Wang DZ;Chen Y;Huang ZP
通讯作者：
Huang ZP

Application of CRISPR-Cas9 gene editing for congenital heart disease.

CRISPR-CAS9基因编辑的应用用于先天性心脏病。