Functional GWAS for LVH using iPS-derived Cardiomyocytes: The HyperGEN ciPS Stud

使用 iPS 衍生心肌细胞进行 LVH 功能性 GWAS：HyperGEN ciPS Stud

• 批准号: 8093625
• 负责人: ULRICH BROECKEL
• 金额: $ 57.01万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093625
• 关键词: Affect; African American; Applications Grants; Biological Models; Blood Cells; Cardiac Myocytes; Cardiovascular Diseases; Caucasians; Caucasoid Race; Cell Line; Cells; Collaborations; Complex; Congestive Heart Failure; DNA; Data; Derivation procedure; Development; Disease; Disease Pathway; Drug Delivery Systems; Early treatment; Epidemiologic Studies; Epidemiology; Ethnic Origin; Etiology; Exhibits; Family; Family Study; Foundations; Future; Generations; Genes; Genetic; Genetic Research; Grant; Human; Hypertension; Individual; International; Intervention; Left Ventricular Hypertrophy; Left Ventricular Mass; Methods; Molecular; Molecular Profiling; Morbidity - disease rate; Myocardial Infarction; National Heart, Lung, and Blood Institute; Pathway interactions; Pharmaceutical Preparations; Phase; Phenotype; Prevention; Procedures; Property; Protocols documentation; Quality Control; Renin-Angiotensin System; Research; Research Infrastructure; Risk Factors; Role; Sampling; Single Nucleotide Polymorphism; Solutions; Stroke; System; Technology; Twin Studies; Variant; Ventricular; abstracting; aging population; base; cell type; cohort; data management; follow-up; genetic epidemiology; genome wide association study; improved; induced pluripotent stem cell; innovation; mortality; new therapeutic target; novel; scale up; stem cell technology; success; trait; treatment strategy

DESCRIPTION (provided by applicant): The overall focus for this grant is to follow-up findings from one of the largest multi-ethnic genome-wide association studies for Left Ventricular Mass (LVM) and Left Ventricular Hypertrophy (LVH). We propose to use induced pluripotent stem cell (IPS) technology to investigate and understand the complex molecular mechanisms and pathways underlying the genetic basis of an increase in LVM leading to LVH as a common and major risk factor for cardiovascular disease. This grant application lays the foundation for extending the epidemiological and genetic research conducted as part of the NHLBI 'Hypertension Genetic Epidemiology Network' - Echo (HyperGEN-ECHO) study, which focuses on the identification of genes for LVH, to a functional level. The HyperGen cohort is one of the largest family-based cohorts with echocardiographic data for both Caucasians and African-Americans. We have performed a family-based GWA study in each ethnicity and identified SNPs and genes related to LVM and other related phenotypes. As common to epidemiologically-based GWA studies, these findings lack functional annotation and the interplay between identified SNPs remains to be elucidated. The advent of human induced pluripotent stem cell (iPSC) technology provides a experimental solution to this problem. Human iPSC-derived cardiomyocytes exhibit properties highly similar to their primary counterparts, thus can be used as a model system for the required functional analysis. We propose to further improve protocols for the efficient generation of iPSCs and cardiomyocytes (Phase I); develop and scale-up the technology and infrastructure to produce iPSCs and cardiomyocytes for 100 of the most informative families in both African-Americans and Caucasians (250 donors) (Phase II); derive iPSCs and cardiomyocytes, and study the molecular changes associated with the development of LVH by analyzing expression changes under various conditions. Using family-based eQTL analysis, we will study the impact of DNA variation on these molecular changes associated with SNPs identified in GWAS (Phase III). Novel analysis methods will aim to identify new disease pathways as future targets for therautic interventions. (End of Abstract)

描述（由申请人提供）： 这笔赠款的总体重点是对左心室质量 (LVM) 和左心室肥大 (LVH) 最大的多种族全基因组关联研究之一的后续发现。我们建议使用诱导多能干细胞 (IPS) 技术来研究和了解 LVM 增加导致 LVH 作为心血管疾病的常见和主要危险因素的遗传基础的复杂分子机制和途径。这项拨款申请为扩展 NHLBI“高血压遗传流行病学网络”-Echo (HyperGEN-ECHO) 研究的一部分进行的流行病学和遗传学研究奠定了基础，该研究的重点是识别 LVH 基因至功能水平。 HyperGen 队列是最大的基于家庭的队列之一，拥有白人和非裔美国人的超声心动图数据。我们在每个种族中进行了一项基于家庭的 GWA 研究，并确定了与 LVM 和其他相关表型相关的 SNP 和基因。与基于流行病学的 GWA 研究一样，这些发现缺乏功能注释，并且已识别的 SNP 之间的相互作用仍有待阐明。人类诱导多能干细胞（iPSC）技术的出现为这一问题提供了实验性的解决方案。人 iPSC 衍生的心肌细胞表现出与原代心肌细胞高度相似的特性，因此可以用作所需功能分析的模型系统。我们建议进一步改进高效生成 iPSC 和心肌细胞的方案（第一阶段）；开发并扩大技术和基础设施，为 100 个信息最丰富的非裔美国人和白种人家庭（250 个捐赠者）生产 iPSC 和心肌细胞（第二阶段）；衍生 iPSC 和心肌细胞，并通过分析各种条件下的表达变化来研究与 LVH 发展相关的分子变化。使用基于家族的 eQTL 分析，我们将研究 DNA 变异对与 GWAS（第三阶段）中确定的 SNP 相关的分子变化的影响。新的分析方法将旨在确定新的疾病途径作为未来治疗干预的目标。 （摘要完）