Genetic Regulation of Human Beta Cell Destruction

人类β细胞破坏的基因调控

基本信息

  • 批准号:
    8813679
  • 负责人:
  • 金额:
    $ 311.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-30 至 2019-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The development of Type 1 Diabetes (T1D) relies on complex interrelationships between cells of the immune system [e.g., DC, CD8+ T cells] and genes imparting susceptibility or resistance to the disease that underlie the autoimmune destruction of insulin producing pancreatic β cells. While a broad body of evidence certainly exists to support this notion (and we ourselves believe it true), the exact mechanism by which autoimmune β cell destruction is facilitated remains unclear. In addition, the relative contributions of each facet (i.e., cells, genes) play in the process remain, to a large extent, unknown. Mechanistic studies of T1D-associated susceptibility alleles are complicated by polygenic inheritance such that no two individuals are truly alike. Hence, studies are severely hampered by a lack of power in populations, and the inability to isolate the functional impact of a variant to a specific cell type. Here we present a solution that focuses on individual alleles usin an innovative isogenic mode that takes advantage of cutting edge technologies. We have created an experimental platform to study how specific genetic risk variants precipitate immune dysregulation leading to cytotoxic CD8+ T lymphocyte (CTL) activation and β cell destruction. We hypothesize that genetically regulated defects in PTPN22 promote; i) immunogenic DC, ii) TH1 responses, iii) pancreatic vascular inflammation and CTL homing, and iv) pathogenic CTL activity towards β cells coupled with reduced activation induced CTL death: each of these tenants form an aim of this grant. Further, we posit that defects reach full potential when immune cells and endothelial cells are excessively sensitive to activation by endogenous or exogenous factors that stimulate inflammation, thus linking environment and immunogenetics in T1D. Here we will utilize a novel experimental pipeline where PTPN22R (T1D resistant), PTPN22W (T1D susceptible) or PTPN22 deletion (PTPN22-/-) alleles are carried by isogenic human immune and endothelial cells engineered from induced pluripotent stem cells [iPSC]. The iPSC system allows exquisite control of T1D disease alleles, where the susceptible allele can be replaced by the resistant allele (and vice versa) providing a constant genetic background upon which effects of a single risk allotype can be studied without complicating epistatic effects, in a manner analogous to studies in genetically modified mice. This system proposed here will provide an unprecedented capacity to interrogate molecular and cellular interactions under isogenic conditions to provide mechanistic understanding of how PTPN22 alleles regulate individual steps of T1D pathogenesis and how those steps interrelate to bring upon T1D onset. Importantly, this study will also lay the groundwork for future investigations of single or multipl T1D susceptibility genes using this innovative strategy.


项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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CLAYTON E MATHEWS其他文献

CLAYTON E MATHEWS的其他文献

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{{ truncateString('CLAYTON E MATHEWS', 18)}}的其他基金

Discovery and Roles of In Situ Islet Neoantigens in Human Type 1 Diabetes
原位胰岛新抗原在人类 1 型糖尿病中的发现及其作用
  • 批准号:
    10589578
  • 财政年份:
    2023
  • 资助金额:
    $ 311.66万
  • 项目类别:
Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes
确定 1 型糖尿病中 IFIH1 疾病相关变异对 β 细胞和免疫反应的机制
  • 批准号:
    10903049
  • 财政年份:
    2023
  • 资助金额:
    $ 311.66万
  • 项目类别:
Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes
确定 1 型糖尿病中 IFIH1 疾病相关变异对 β 细胞和免疫反应的机制
  • 批准号:
    10417267
  • 财政年份:
    2020
  • 资助金额:
    $ 311.66万
  • 项目类别:
Organ Specific Project
器官特定项目
  • 批准号:
    10685591
  • 财政年份:
    2020
  • 资助金额:
    $ 311.66万
  • 项目类别:
Organ Specific Project
器官特定项目
  • 批准号:
    10259784
  • 财政年份:
    2020
  • 资助金额:
    $ 311.66万
  • 项目类别:
Organ Specific Project
器官特定项目
  • 批准号:
    10118877
  • 财政年份:
    2020
  • 资助金额:
    $ 311.66万
  • 项目类别:
Multi-omic 3D tissue maps for a Human BioMolecular Atlas
人类生物分子图谱的多组学 3D 组织图谱
  • 批准号:
    10649957
  • 财政年份:
    2020
  • 资助金额:
    $ 311.66万
  • 项目类别:
Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes
确定 1 型糖尿病中 IFIH1 疾病相关变异对 β 细胞和免疫反应的机制
  • 批准号:
    10263321
  • 财政年份:
    2020
  • 资助金额:
    $ 311.66万
  • 项目类别:
mt-Nd2 and Resistance to Autoimmune Diabetes
mt-Nd2 与自身免疫性糖尿病的抵抗力
  • 批准号:
    7998873
  • 财政年份:
    2010
  • 资助金额:
    $ 311.66万
  • 项目类别:
mt-Nd2 and Resistance to Autoimmune Diabetes
mt-Nd2 与自身免疫性糖尿病的抵抗力
  • 批准号:
    8297271
  • 财政年份:
    2006
  • 资助金额:
    $ 311.66万
  • 项目类别:

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非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
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