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：
10436487
负责人：
Ioannis Karakikes
金额：
$ 13.49万
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 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436487
关键词：
Accounting Address Animal Model Biological Biological Models CRISPR/Cas technology Calcium Cardiac Cardiac Myocytes Case Study Cell model Chronic Complex Data Diagnosis Dilated Cardiomyopathy Disease Disease model Disease susceptibility Endoplasmic Reticulum Environment Event Family Functional disorder Gene Mutation Generations Genes Genetic Genetic Screening Genetic Transcription Genotype Goals Heart failure Homeostasis Human Impairment In Vitro Individual Knowledge Lead Link Mediating Modeling Molecular Mutation Pathogenesis Pathogenicity Pathologic Pathologic Processes Patients Pharmacology Phenotype Play Population Positioning Attribute Prevalence Proteins Regulator Genes Research Proposals Role Running Signal Pathway Signal Transduction Source System Technology Testing Transgenic Animals Transgenic Mice Translating Troponin T Variant base design disease phenotype endoplasmic reticulum stress familial dilated cardiomyopathy genetic variant genome editing heart cell human model in vivo in vivo Model induced pluripotent stem cell induced pluripotent stem cell technology insight interdisciplinary approach mouse model multidisciplinary new technology next generation sequencing novel phospholamban precision medicine response sound stem cell biology stem cells targeted treatment

Accounting Address Animal Model Biological Biological Models CRISPR/Cas technology Calcium Cardiac Cardiac Myocytes Case Study Cell model Chronic Complex Data Diagnosis Dilated Cardiomyopathy Disease Disease model Disease susceptibility Endoplasmic Reticulum Environment Event Family Functional disorder Gene Mutation Generations Genes Genetic Genetic Screening Genetic Transcription Genotype Goals Heart failure Homeostasis Human Impairment In Vitro Individual Knowledge Lead Link Mediating Modeling Molecular Mutation Pathogenesis Pathogenicity Pathologic Pathologic Processes Patients Pharmacology Phenotype Play Population Positioning Attribute Prevalence Proteins Regulator Genes Research Proposals Role Running Signal Pathway Signal Transduction Source System Technology Testing Transgenic Animals Transgenic Mice Translating Troponin T Variant base design disease phenotype endoplasmic reticulum stress familial dilated cardiomyopathy genetic variant genome editing heart cell human model in vivo in vivo Model induced pluripotent stem cell induced pluripotent stem cell technology insight interdisciplinary approach mouse model multidisciplinary new technology next generation sequencing novel phospholamban precision medicine response sound stem cell biology stem cells targeted treatment

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项目摘要

Project Summary Dilated cardiomyopathy (DCM) is a leading cause of heart failure. Genetic DCM, which runs in families, is now more commonly diagnosed, accounting for up to half of the reported cases. Despite the progress in unraveling the genetic basis of DCM, there is still a large gap in our understanding of the molecular events and signaling pathways that lead from a mutation to diverse disease phenotypes. The recent advent of new technologies, such as patient-specific induced pluripotent stem cells (iPSCs) and genome editing (CRISPR/Cas9), provide an unprecedented opportunity to study associations between genetic variability and disease susceptibility. By combining these breakthrough technologies, we are now poised to address one of the most critical issues in familial DCM, namely, the genotype-phenotype relationship from the ever-growing number of DCM-associated gene mutations. The overarching goal of our proposal is to utilize a multidisciplinary approach that integrates patient-specific iPSCs, genome editing, genetic screens, next generation sequencing technologies and transgenic animal models to gain novel insights into genotype-phenotype associations, and to dissect the molecular mechanism of genetic DCM pathogenesis. Our preliminary studies have implicated the activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) in the pathogenesis of DCM in a model of patient-specific iPSC-CMs. The central hypothesis of the revised proposal is that certain DCM mutations alter Ca2+ homeostasis and cause chronic ER stress, leading to prolonged activation of the UPR signaling. We will pursue three specific aims. In aim 1: we will establish an experimental platform to study the genotype- phenotype association of cardiac troponin T (TNNT2) and phospholamban (PLN) gene variants associated with DCM; in aim 2: we will decipher the role of ER stress and UPR activation in genetic DCM; and in aim 3: interrogate the mechanisms of DCM pathogenesis associated with TNNT2 mutations in vivo. We have assembled a multi-disciplinary team with extensive complementary and integrated expertise. We have provided compelling preliminary data to support the soundness of our hypothesis-driven research proposal, and we are well positioned to achieve the project goals within five years. If successful, our studies will provide a new paradigm for understanding the pathogenesis and treatment of familial DCM.

项目摘要扩张的心肌病（DCM）是心力衰竭的主要原因。在家庭中运行的遗传DCM现在已经更常见的是，最多占报告病例的一半。尽管取得了进展 DCM的遗传基础，我们对分子事件和信号的理解仍然存在很大的差距从突变到多种疾病表型的途径。最近的新技术出现例如患者特异性诱导的多能干细胞（IPSC）和基因组编辑（CRISPR/CAS9），提供一个前所未有的机会，可以研究遗传变异性与疾病敏感性之间的关联。经过结合了这些突破性技术，我们现在准备解决最关键的问题之一家族性DCM，即来自不断增长的DCM相关的基因型 - 表型关系基因突变。我们建议的总体目标是利用一种整合的多学科方法患者特异性IPSC，基因组编辑，遗传筛选，下一代测序技术和转基因动物模型，以获取对基因型 - 表型关联的新见解，并剖析遗传DCM发病机理的分子机制。我们的初步研究暗示了激活在模型中DCM发病机理中内质网（ER）中未展开的蛋白质反应（UPR）特定于患者的IPSC-CMS。修订的提案的中心假设是某些DCM突变改变Ca2+稳态并引起慢性ER应力，从而导致UPR信号的延长激活。我们将追求三个具体目标。在AIM 1中：我们将建立一个实验平台来研究基因型心脏肌钙蛋白T（TNNT2）和磷脂（PLN）基因变异的表型关联与DCM；在AIM 2中：我们将破译ER应力和UPR激活在遗传DCM中的作用；在AIM 3中：询问与体内TNNT2突变相关的DCM发病机理的机制。我们有组建了一个具有广泛互补和综合专业知识的多学科团队。我们有提供了令人信服的初步数据，以支持我们假设驱动的研究建议的合理性，而且，我们在五年内实现了项目目标的好处。如果成功，我们的研究将提供一种新的范式，用于了解家族性DCM的发病机理和治疗。