Genetic contribution to loss of B cell anergy during development of type 1 diabetes

1 型糖尿病发展过程中 B 细胞无反应性丧失的遗传因素

基本信息

  • 批准号:
    10431828
  • 负责人:
  • 金额:
    $ 13.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract This proposal for a five-year mentored research career development project focuses on elucidating the role of the type 1 diabetes (T1D) PTPN2 risk allele in loss of B cell anergy. Previously B cells bearing antigen receptors with high affinity for insulin were found only in the anergic B cell compartment of healthy individuals. Importantly, these cells leave this compartment in a proportion of first-degree relatives (FDRs), and in all autoantibody positive pre-diabetics and recent onset diabetics. Departure of these autoreactive anergic B cells in FDRs was shown to be associated with high risk T1D HLA alleles, and three high risk non-HLA alleles, including INS (rs689), PTPN2 (rs1893217), and IKZF3 (rs2872507). Of the three non-HLA risk alleles, only PTPN2 has been previously shown to be a negative regulator of signaling. However these previous studies were completed in mice, not humans, and their exact mechanism by which they contribute to development and signaling has yet to be determined. This application proposes to determine the effect of the T1D risk variant of PTPN2 in maintenance of B cell anergy. Aim 1 will explore the effect of the risk variant on the phenotype of the B cell compartment in FDRs of T1D patients and their response to stimulation. Aim 2 will explore the relationship of loss of anergic B cells with the high risk T1D genotype allele, Ptpn2, using a reductionist mouse model. The potential impact of these studies will lie in understanding how risk alleles conspire to undermine maintenance of immune tolerance to autoantigens in T1D. The candidate is an Instructor at the Barbara Davis Center for Diabetes and has brought together a diverse team of experts to serve on her advisory committee. The outlined proposal builds upon the candidate's previous research but will enable advancement of technical and analytical skills utilizing state-of-the-art technologies and will allow pursuit of new avenues of B cell research. In addition, the training and development plan is comprehensive and tailored to her needs, which will enable her to transition to independence as a highly productive veterinary scientist in the field of autoimmunity.
项目总结/文摘

项目成果

期刊论文数量(0)
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Mia Smith其他文献

Mia Smith的其他文献

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{{ truncateString('Mia Smith', 18)}}的其他基金

Decoding the B cell endotype in early onset type 1 diabetes
解读早发 1 型糖尿病中的 B 细胞内型
  • 批准号:
    10294155
  • 财政年份:
    2021
  • 资助金额:
    $ 13.64万
  • 项目类别:
Genetic contribution to loss of B cell anergy during development of type 1 diabetes
1 型糖尿病发展过程中 B 细胞无反应性丧失的遗传因素
  • 批准号:
    10178141
  • 财政年份:
    2020
  • 资助金额:
    $ 13.64万
  • 项目类别:
Genetic contribution to loss of B cell anergy during development of type 1 diabetes
1 型糖尿病发展过程中 B 细胞无反应性丧失的遗传因素
  • 批准号:
    10055413
  • 财政年份:
    2020
  • 资助金额:
    $ 13.64万
  • 项目类别:
Genetic contribution to loss of B cell anergy during development of type 1 diabetes
1 型糖尿病发展过程中 B 细胞无反应性丧失的遗传因素
  • 批准号:
    10647749
  • 财政年份:
    2020
  • 资助金额:
    $ 13.64万
  • 项目类别:
Genetic risk alleles as drivers of loss of anergic B cells in autoimmunity
遗传风险等位基因是自身免疫中无能 B 细胞丧失的驱动因素
  • 批准号:
    9305774
  • 财政年份:
    2016
  • 资助金额:
    $ 13.64万
  • 项目类别:

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