Gene-by-environment interactions that affect exposure-mediated congenital heart disease

影响暴露介导的先天性心脏病的基因与环境相互作用

基本信息

  • 批准号:
    10655611
  • 负责人:
  • 金额:
    $ 62.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-10 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract We propose to exploit unique features of the Atlantic killifish model system to elucidate the interaction of genetic variation and environmental exposures in the etiology of congenital heart disease (CHD). This complex human disease encompasses a suite of structural and functional deficits and is the most common human congenital malformation worldwide. The etiology of CHD is poorly understood, but appears to involve both genetic and environmental risk factors, including exposure to environmental chemicals. The Atlantic killifish (Fundulus heteroclitus) is a novel population-based model system that harbors substantial genetic diversity and exhibits chemical-induced cardiovascular disease states that mimic substantial aspects of CHD in humans. Killifish inhabit urbanized environments that are polluted by mixtures of chemicals including polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs). Urban and non-urban populations vary profoundly in their sensitivity to CHD caused by exposure to these compounds. We propose to use this unique and powerful system to explore gene-environment interactions associated with CHD, expanding on our successful use of the Quantitative Trait Loci (QTL) approach in this species. A particularly compelling feature of this model is that natural selection has increased the frequency of otherwise rare variants that influence sensitivity to these (and potentially other) important classes of pollutants. Our previous data reveal some regions of the genome that affect fitness in polluted environments, and contribute to variation in sensitivity to CHD. The overall objective of the proposed research is to determine the genes and pathways harboring genetic variation that controls sensitivity to PCB- and PAH-induced CHD. We will test for genetic associations through genome-wide genotyping of phenotyped animals in replicate families bred using QTL strategies and exposed to PCB and PAHs. Experiments will test for genetic association with multiple specific structural and functional deficits that define the suite of CHD phenotypes. This QTL mapping will include 1) multiple genetic backgrounds, 2) multiple CHD-associated chemicals, each with different hypothesized mechanisms of action, and 3) multiple exposure levels. We will test whether the different CHD features are associated with unique or shared variants in different genetic backgrounds, and whether disease-associated variants are unique or shared among structurally diverse classes of chemicals that may cause CHD by different mechanisms. We will evaluate the relevance of CHD-associated variants by testing whether they are associated with variable fitness between polluted and clean environments, focus inference of candidate genes using eQTL mapping, and test hypothesized associations using genome editing by CRISPR-Cas9 technology. This research in a population-based vertebrate model will reveal mechanisms underlying gene- environment interactions involved in determining susceptibility to CHD, a common congenital condition.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Mark E Hahn其他文献

Mark E Hahn的其他文献

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{{ truncateString('Mark E Hahn', 18)}}的其他基金

Understanding the origins and mechanisms of aryl hydrocarbon receptor promiscuity
了解芳烃受体混杂的起源和机制
  • 批准号:
    10679532
  • 财政年份:
    2023
  • 资助金额:
    $ 62.37万
  • 项目类别:
Mechanisms Controlling Sensitivity and Resistance to Dioxin-like Compounds: Role of AIP
控制对二恶英类化合物的敏感性和耐受性的机制:AIP 的作用
  • 批准号:
    10538943
  • 财政年份:
    2022
  • 资助金额:
    $ 62.37万
  • 项目类别:
Gene-by-environment interactions that affect exposure-mediated congenital heart disease
影响暴露介导的先天性心脏病的基因与环境相互作用
  • 批准号:
    10216463
  • 财政年份:
    2021
  • 资助金额:
    $ 62.37万
  • 项目类别:
Project 3: Cellular and Molecular Mechanisms Underlying Long-term Effects of Early Life Exposure to HAB Toxins
项目 3:生命早期接触 HAB 毒素造成长期影响的细胞和分子机制
  • 批准号:
    10434783
  • 财政年份:
    2018
  • 资助金额:
    $ 62.37万
  • 项目类别:
Project 3: Cellular and Molecular Mechanisms Underlying Long-term Effects of Early Life Exposure to HAB Toxins
项目 3:生命早期接触 HAB 毒素造成长期影响的细胞和分子机制
  • 批准号:
    10223309
  • 财政年份:
    2018
  • 资助金额:
    $ 62.37万
  • 项目类别:
microRNAs in Developmental Toxicology
发育毒理学中的 microRNA
  • 批准号:
    7642973
  • 财政年份:
    2009
  • 资助金额:
    $ 62.37万
  • 项目类别:
Mechanisms of Embryo Response to Oxidative Stress
胚胎对氧化应激的反应机制
  • 批准号:
    8244524
  • 财政年份:
    2009
  • 资助金额:
    $ 62.37万
  • 项目类别:
Mechanisms of Embryo Response to Oxidative Stress
胚胎对氧化应激的反应机制
  • 批准号:
    8051862
  • 财政年份:
    2009
  • 资助金额:
    $ 62.37万
  • 项目类别:
Mechanisms of Embryo Response to Oxidative Stress
胚胎对氧化应激的反应机制
  • 批准号:
    8450175
  • 财政年份:
    2009
  • 资助金额:
    $ 62.37万
  • 项目类别:
Mechanisms of Embryo Response to Oxidative Stress
胚胎对氧化应激的反应机制
  • 批准号:
    7655110
  • 财政年份:
    2009
  • 资助金额:
    $ 62.37万
  • 项目类别:

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