Sarcomeric Regulation of Signal Transduction and Cardiomyopathy

信号转导和心肌病的肌节调节

基本信息

批准号：
9976127
负责人：
Yuxuan Guo
金额：
$ 11.16万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976127
关键词：
Ablation Actinin Actins Affect Animals Binding CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiomyopathies Cells Chromatin Code Cytoskeleton Data Defect Dependovirus Dilatation - action Dilated Cardiomyopathy Disease Disease model Education F-Actin Fibrosis Gene Expression Profile Genes Genetic Genetic Transcription Goals Grant Heart Heart Abnormalities Heart Diseases Human Impairment Individual Inherited Knock-out Knowledge Lead Mediating Mediator of activation protein Mentorship Missense Mutation Modeling Molecular Mosaicism Mus Mutagenesis Mutation Myocardial Contraction Myocardial dysfunction Myosin Heavy Chains Nuclear Nuclear Translocation Occupations Pathogenesis Pathway interactions Physiological Play Regulation Research Research Proposals Role Sarcomeres Scientist Secondary to Serum Response Factor Signal Transduction Structure Technology Testing Therapeutic Therapeutic Effect Training Transcriptional Regulation Treatment Efficacy Ventricular base cardiac muscle disease cardiac tissue engineering career development cofactor crosslink driving force familial dilated cardiomyopathy genome editing induced pluripotent stem cell inherited cardiomyopathy insight novel novel therapeutic intervention polymerization prevent targeted treatment therapeutic development transcription factor transcriptomics

Ablation Actinin Actins Affect Animals Binding CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiomyopathies Cells Chromatin Code Cytoskeleton Data Defect Dependovirus Dilatation - action Dilated Cardiomyopathy Disease Disease model Education F-Actin Fibrosis Gene Expression Profile Genes Genetic Genetic Transcription Goals Grant Heart Heart Abnormalities Heart Diseases Human Impairment Individual Inherited Knock-out Knowledge Lead Mediating Mediator of activation protein Mentorship Missense Mutation Modeling Molecular Mosaicism Mus Mutagenesis Mutation Myocardial Contraction Myocardial dysfunction Myosin Heavy Chains Nuclear Nuclear Translocation Occupations Pathogenesis Pathway interactions Physiological Play Regulation Research Research Proposals Role Sarcomeres Scientist Secondary to Serum Response Factor Signal Transduction Structure Technology Testing Therapeutic Therapeutic Effect Training Transcriptional Regulation Treatment Efficacy Ventricular base cardiac muscle disease cardiac tissue engineering career development cofactor crosslink driving force familial dilated cardiomyopathy genome editing induced pluripotent stem cell inherited cardiomyopathy insight novel novel therapeutic intervention polymerization prevent targeted treatment therapeutic development transcription factor transcriptomics

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项目摘要

PROJECT SUMMARY/ABSTRACT Sarcomeres are specialized cytoskeletal structures in cardiomyocytes (CMs) that generate the force driving the heart contraction. Mutations in genes coding sarcomere components, or “sarcomere mutations”, often cause inherited cardiomyopathies including most cases of inherited dilated cardiomyopathy (DCM). Sarcomere mutations are believed to impair CM contraction, thereby causing the contractile defects in DCM hearts. How- ever, whether other aspects of sarcomere function contribute to DCM pathogenesis has been incompletely studied. This knowledge gap prevents comprehensive understanding of DCM pathogenesis and limits the de- velopment of effective therapeutic strategies. This research proposal tests the overarching hypothesis that sarcomeres regulate signal transduction, which contributes to the pathogenesis of DCM. Specifically, Dr. Guo will dissect the mechanisms by which ac- tinin-2 (ACTN2) mutations perturb serum response factor (SRF) signaling through SRF cofactors MKL1/2, and the contribution of this pathway to DCM. This hypothesis will be tested through three Specific Aims. Aim 1 will study whether ACTN2 activates MKL-SRF signaling by promoting actin polymerization in CMs. Aim 2 will de- termine if then ACTN2-MKL1/2 pathway regulates transcription in CMs by affecting SRF-chromatin binding. Aim 3 will test the hypothesis that ACTN2-MKL-SRF signaling contributes to the pathogenesis of DCM caused by ACTN2 missense mutations. This project will reveal novel molecular insights about DCM pathogenesis. These insights may lead to new therapeutic approaches to treat DCM. This project is built upon state-of-the-art technologies such as adeno-associated virus (AAV)-delivered CRISPR/Cas9-based somatic mutagenesis and cardiac genetic mosaics analysis that were co-developed by Dr. Guo. K99/R00 will further sponsor training in induced pluripotent stem cells (hiPSCs), genome editing, sin- gle-cell transcriptomics and engineered heart tissues, which together with Dr. Guo’s past expertise will estab- lish a powerful and comprehensive technical platform for successful independent research. This grant will also support Dr. Guo’s education from a mentorship team of world-class scientists with relevant expertise and facili- tate Dr. Guo’s career development activities as he transitions toward independence.

项目摘要/摘要肉瘤是产生力驱动力的心肌细胞（CMS）中的专门细胞骨架结构心脏收缩。编码肌膜成分或“肌节突变”的基因突变，通常导致遗传性心肌病，包括大多数遗传性扩张心肌病例（DCM）。肌节人们认为突变会损害CM收缩，从而导致DCM心脏的收缩缺陷。如何- 从来没有肌节功能的其他方面是否有助于DCM发病机理 Studiod。这种知识差距阻止了对DCM发病机理的全面理解，并限制了有效治疗策略的速度。该研究建议检验了肉瘤调节信号转导的总体假设，这有助于DCM的发病机理。具体而言，郭博士将剖析采用的机制 Tinin-2（ACTN2）突变通过SRF辅因子MKL1/2和该途径对DCM的贡献。该假设将通过三个特定目标进行检验。目标1意志研究ACTN2是否通过促进CMS中的肌动蛋白聚合来激活MKL-SRF信号传导。 AIM 2将 termine如果然后ACTN2-MKL1/2途径通过影响SRF-染色质结合来调节CMS中的转录。 AIM 3将检验ACTN2-MKL-SRF信号传导有助于DCM引起的发病机理的假设通过ACTN2错义突变。该项目将揭示有关DCM发病机理的新分子见解。这些见解可能会导致治疗DCM的新治疗方法。该项目建立在最先进的技术之上，例如腺相关病毒（AAV）延迟基于CRISPR/CAS9的体细胞诱变和心脏遗传马赛克分析是由共同开发的郭博士。 K99/R00将进一步赞助诱导的多能干细胞（HIPSC），基因组编辑，SIN- GLE细胞转录组学和工程性心脏组织，与Guo博士的过去专业知识一起，为成功的独立研究提供了一个强大而全面的技术平台。这笔赠款也将支持Guo博士的教育团队，由世界一流的科学家组成，具有相关的专业知识和促进泰特·郭博士（Tate Guo）向独立过渡时的职业发展活动。