Genetic Signals in Ventricular Hypertrophy

心室肥大的遗传信号

基本信息

  • 批准号:
    10454851
  • 负责人:
  • 金额:
    $ 53.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-02-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Left ventricular hypertrophy (LVH) is a prevalent condition that conveys increased risk for cardiovascular events and all-cause mortality. Studies from our lab and others have genetic causes for Mendelian forms of LVH. Pathogenic variants in sarcomere protein genes account for ~50% of familial hypertrophic cardiomyopathy (HCM) and ~30% sporadic HCM. LVH also occurs from pathogenic variants in non-sarcomere genes including PRKAG2, GLA and LAMP2. Despite this progress, detailed genetic analyses of all known LVH genes fail to identify a pathogenic or likely pathogenic variant in >50% of individuals with isolated LVH that is unexplained (denoted as iLVH). To address this gap in knowledge we have harnessed whole genome sequencing (WGS) to comprehensively explore genetic cause of iLVH. Under the aegis of NIH TOPMed program (X01HL143310, PI, J.G. Seidman) we will obtain WGS data from 650 iLVH subjects and comprehensive transcriptional profiling (RNAseq) of associated iLVH tissues from these subjects. From WGS data we will identify rare and common variants in coding and noncoding sequences that may cause or contribute to iLVH. We will also consider the involvement of mitochondrial variants, somatic mosaicism, and/or pathogens in iLVH. We will characterize the functional impact of iLVH variants using induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and new strategies to assess sarcomere performance and cardiomyocyte biology. From our analyses of isogenic iPSC-CMs with pathogenic variants in established LVH genes we defined precise abnormalities in sarcomere contraction and relaxation and cellular energetics. We will expand these analyses to studies of other pathogenic variants in established LVH genes so as to develop a reference dataset to which we will compare functional studies of novel variants identified in iLVH subjects. Parallel analyses of variants of unknown significance (VUS) in established LVH genes aim to improve the clinical interpretation of these abundant and enigmatic variants. By combining functional data with RNAseq analyses from cardiac tissues (obtained from LVH and iLVH subjects) and RNAseq of PSC-CMs we will begin to discern transcriptional responses to LVH and iLVH variants. We expect these studies will expand our understanding of the genetic architecture of iLVH and hypertrophic mechanisms and thereby promote the development of rationale therapeutics for LVH patients. These data will also enrich our insights of sarcomere physiology that enables life-long cardiomyocyte function or that incites disease. More broadly these studies will contribute to information about regulatory elements that modulate cardiac gene expression. Specifically we will: 1. Analyze whole genome sequences and RNAseq for variants associated with iLVH 2. Identify mechanisms induced by pathogenic variants in LVH tissues and iPSC-CMs. 3. Define the pathogenicity of coding and non-coding VUS in LVH and iLVH genes.
摘要 左心室肥大(LVH)是一种常见的疾病,它增加了心血管疾病的风险。 事件和全因死亡率。我们实验室的研究和其他人的研究都有孟德尔形式的遗传原因, 左心室肥厚肌节蛋白基因的致病变异占家族性肥厚型心肌病的50% (HCM)和约30%的散发性HCM。LVH也发生于非肌节基因的致病性变异,包括 PRKAG 2、GLA和LAMP 2。尽管取得了这一进展,但对所有已知LVH基因的详细遗传分析未能 在>50%的不明原因的孤立性LVH患者中确定致病性或可能致病性变异 (表示为iLVH)。为了解决这一知识缺口,我们利用全基因组测序(WGS), 全面探讨iLVH的遗传病因。在NIH TOPMed程序(X 01 HL 143310,PI, J.G. Seidman),我们将从650名iLVH受试者中获得WGS数据, 使用RNA测序技术(RNAseq)分析来自这些受试者的相关iLVH组织。从WGS数据中,我们将识别罕见和常见 可能导致或促成iLVH的编码和非编码序列变异。我们亦会考虑 线粒体变异、体细胞嵌合和/或病原体参与iLVH。 我们将使用诱导的多能干细胞衍生物来表征iLVH变体的功能影响。 心肌细胞(iPSC-CM)和评估肌节性能和心肌细胞生物学的新策略。 根据我们对在已建立的LVH基因中具有致病性变体的同基因iPSC-CM的分析,我们定义了 肌节收缩和松弛以及细胞能量学的精确异常。我们将扩大这些 分析已建立的LVH基因中其他致病变异的研究,以开发参考数据集 我们将比较iLVH受试者中鉴定的新变体的功能研究。并行分析 在已建立的LVH基因中,未知意义的变异(VUS)旨在改善LVH的临床解释。 这些丰富而神秘的变体通过将功能数据与来自心脏的RNAseq分析相结合, 我们将开始辨别PSC-CM的组织(从LVH和iLVH受试者获得)和RNAseq 对LVH和iLVH变体的转录应答。 我们预计这些研究将扩大我们对iLVH遗传结构的了解, 从而促进LVH患者合理治疗方法的发展。 这些数据也将丰富我们对肌节生理学的认识,使心肌细胞能够终身发挥功能。 或者引发疾病的东西更广泛地说,这些研究将有助于提供有关调控因素的信息, 调节心脏基因表达。具体而言,我们将: 1.分析全基因组序列和RNAseq中与iLVH相关的变体 2.确定LVH组织和iPSC-CM中致病性变体诱导的机制。 3.定义LVH和iLVH基因中编码和非编码VUS的致病性。

项目成果

期刊论文数量(86)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
[Using molecular genetics to guide the diagnosis and treatment of hypertrophic cardiomyopathy].
分子遗传学指导肥厚型心肌病的诊治[J].
  • DOI:
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Wang,Li-bin;Seidman,JG;Seidman,ChristineE
  • 通讯作者:
    Seidman,ChristineE
Quantification of microRNA expression with next-generation sequencing.
  • DOI:
    10.1002/0471142727.mb0417s103
  • 发表时间:
    2013-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Eminaga, Seda;Christodoulou, Danos C;Vigneault, Francois;Church, George M;Seidman, J G
  • 通讯作者:
    Seidman, J G
Variation in the 4q25 chromosomal locus predicts atrial fibrillation after coronary artery bypass graft surgery.
  • DOI:
    10.1161/circgenetics.109.849075
  • 发表时间:
    2009-10
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Body SC;Collard CD;Shernan SK;Fox AA;Liu KY;Ritchie MD;Perry TE;Muehlschlegel JD;Aranki S;Donahue BS;Pretorius M;Estrada JC;Ellinor PT;Newton-Cheh C;Seidman CE;Seidman JG;Herman DS;Lichtner P;Meitinger T;Pfeufer A;Kääb S;Brown NJ;Roden DM;Darbar D
  • 通讯作者:
    Darbar D
High-throughput multiplex sequencing of miRNA.
  • DOI:
    10.1002/0471142905.hg1112s73
  • 发表时间:
    2012-04
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Vigneault, Francois;Ter-Ovanesyan, Dmitry;Alon, Shahar;Eminaga, Seda;C Christodoulou, Danos;Seidman, J G;Eisenberg, Eli;M Church, George
  • 通讯作者:
    M Church, George
The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle.
  • DOI:
    10.1161/circgenetics.116.001534
  • 发表时间:
    2017-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Saddic LA;Sigurdsson MI;Chang TW;Mazaika E;Heydarpour M;Shernan SK;Seidman CE;Seidman JG;Aranki SF;Body SC;Muehlschlegel JD
  • 通讯作者:
    Muehlschlegel JD
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JONATHAN G SEIDMAN其他文献

JONATHAN G SEIDMAN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('JONATHAN G SEIDMAN', 18)}}的其他基金

Molecular Causes of Down Syndrome Associated Congenital Heart Disease and Other Phenotypes
唐氏综合症相关先天性心脏病和其他表型的分子原因
  • 批准号:
    9894531
  • 财政年份:
    2019
  • 资助金额:
    $ 53.57万
  • 项目类别:
Mapping Transcriptional Networks in Cardiac Development
绘制心脏发育中的转录网络
  • 批准号:
    8127892
  • 财政年份:
    2009
  • 资助金额:
    $ 53.57万
  • 项目类别:
Mapping Transcriptional Networks in Cardiac Development
绘制心脏发育中的转录网络
  • 批准号:
    7769128
  • 财政年份:
    2009
  • 资助金额:
    $ 53.57万
  • 项目类别:
Mapping Transcriptional Networks in Cardiac Development
绘制心脏发育中的转录网络
  • 批准号:
    7936097
  • 财政年份:
    2009
  • 资助金额:
    $ 53.57万
  • 项目类别:
Mapping Transcriptional Networks in Cardiac Development
绘制心脏发育中的转录网络
  • 批准号:
    8309994
  • 财政年份:
    2009
  • 资助金额:
    $ 53.57万
  • 项目类别:
Mapping Transcriptional Networks in Cardiac Development
绘制心脏发育中的转录网络
  • 批准号:
    8712538
  • 财政年份:
    2009
  • 资助金额:
    $ 53.57万
  • 项目类别:
SysCODE: PMAGE Technology Development (10 of 10)
SysCODE:PMAGE 技术开发(10 条,共 10 条)
  • 批准号:
    7822160
  • 财政年份:
    2009
  • 资助金额:
    $ 53.57万
  • 项目类别:
Mapping Transcriptional Networks in Cardiac Development
绘制心脏发育中的转录网络
  • 批准号:
    8514049
  • 财政年份:
    2009
  • 资助金额:
    $ 53.57万
  • 项目类别:
Mapping Transcriptional Networks in Cardiac Development
绘制心脏发育中的转录网络
  • 批准号:
    8663738
  • 财政年份:
    2009
  • 资助金额:
    $ 53.57万
  • 项目类别:
Molecular Signaling in Hypertrophic Cardiomyopathy
肥厚型心肌病的分子信号转导
  • 批准号:
    7765553
  • 财政年份:
    2007
  • 资助金额:
    $ 53.57万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
  • 批准号:
    10065645
  • 财政年份:
    2023
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 53.57万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了