A community resource for germline and somatic genetic disease modeling in zebrafish

斑马鱼种系和体细胞遗传疾病模型的社区资源

基本信息

  • 批准号:
    10723158
  • 负责人:
  • 金额:
    $ 89.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

Summary Genome wide associations studies (GWAS) have produced a multitude of candidate genes and loci for a wide range of complex disease and phenotypic traits, but often have not resulted in sufficient mechanistic insight to lead to actionable changes in prevention, diagnosis, or treatment of disease. This is a consequence of key attributes of the underlying genetic effects which can prove difficult to model, specifically: combinatorial interactions between multiple loci, a preponderance of regulatory effects which may act at different times and in in different tissues or organs, and the integration of lifelong multidimensional risk in many of the mapped disease traits. As the field evolves, so other contributions have begun to be recognized at specific loci including; modification of the effects of existing Mendelian genes, more complex gene-gene or gene-environment interactions and a role for somatic variation contributing to diverse chronic diseases. We have successfully overcome these challenges in our existing Zebrafish GWAS Community Resource by creating a pipeline which exploits the strengths of rapid scalability, functional relevance and genomic conservation of the zebrafish model system to generate useful functional annotation of over 100 genes and regulatory loci over the last 7 years. We have defined the disease gene(s) for multiple GWAS loci in parallel and moved the field forward to early mechanistic studies. We now propose to extend this Community Resource, continuing our existing activities while adding key capabilities in a) modeling gene-gene and gene environment interactions to further explore the complex genetics of numerous common diseases and the b) definitive modeling of somatic variation including efficient transplantation studies to fully understand the role of somatic variation in disease. These new capabilities also directly address ongoing requests from the human genetics community for which the resource was originally developed. As a consortium, we will continue to push forward the capabilities of the zebrafish as a model organism in this field and as costs drop, the number of diseases/loci that we will be able to functionally annotate will only grow through the duration of the proposal. Importantly, we will be able to deliver a comprehensive package of annotated candidate genes and interactions back to our collaborators in the human genetics community to enhance the impact and insight derived from their studies. For this renewal application, we propose the following Specific Aims: Aim 1 - Functionally analyze loci from multiple GWAS studies on blood, liver, heart and vessel traits, optimizing assay development and gene editing using CRISPR-Cas9 technology in zebrafish. Aim 2 - Quantitatively characterize gene-gene and gene-environment interactions where these have been implicated in human genetics Aim 3 - Modeling the role of somatic variation at GWAS loci in chronic disease
总结

项目成果

期刊论文数量(0)
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Wolfram Goessling其他文献

Wolfram Goessling的其他文献

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{{ truncateString('Wolfram Goessling', 18)}}的其他基金

The Role of Macrophages in Hepatobiliary Development
巨噬细胞在肝胆发育中的作用
  • 批准号:
    10680846
  • 财政年份:
    2023
  • 资助金额:
    $ 89.62万
  • 项目类别:
The role of liver progenitor cells in liver regeneration
肝祖细胞在肝再生中的作用
  • 批准号:
    10607301
  • 财政年份:
    2023
  • 资助金额:
    $ 89.62万
  • 项目类别:
Metabolic Regulation of Liver Growth
肝脏生长的代谢调节
  • 批准号:
    9975140
  • 财政年份:
    2016
  • 资助金额:
    $ 89.62万
  • 项目类别:
Metabolic Regulation of Liver Growth
肝脏生长的代谢调节
  • 批准号:
    9765300
  • 财政年份:
    2016
  • 资助金额:
    $ 89.62万
  • 项目类别:
Metabolic Regulation of Liver Growth
肝脏生长的代谢调节
  • 批准号:
    9315803
  • 财政年份:
    2016
  • 资助金额:
    $ 89.62万
  • 项目类别:
A Community Zebrafish Resource for Modeling GWAS Biology
用于 GWAS 生物学建模的社区斑马鱼资源
  • 批准号:
    8840336
  • 财政年份:
    2014
  • 资助金额:
    $ 89.62万
  • 项目类别:
A Community Zebrafish Resource for Modeling GWAS Biology
用于 GWAS 生物学建模的社区斑马鱼资源
  • 批准号:
    8609133
  • 财政年份:
    2014
  • 资助金额:
    $ 89.62万
  • 项目类别:
A Community Zebrafish Resource for Modeling GWAS Biology
用于 GWAS 生物学建模的社区斑马鱼资源
  • 批准号:
    9763679
  • 财政年份:
    2014
  • 资助金额:
    $ 89.62万
  • 项目类别:
A Community Zebrafish Resource for Modeling GWAS Biology
用于 GWAS 生物学建模的社区斑马鱼资源
  • 批准号:
    10225566
  • 财政年份:
    2014
  • 资助金额:
    $ 89.62万
  • 项目类别:
Estrogen Regulation of Hepatic Growth
雌激素对肝脏生长的调节
  • 批准号:
    8850849
  • 财政年份:
    2011
  • 资助金额:
    $ 89.62万
  • 项目类别:

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