Elucidating Lymphocyte Allelic Exclusion Mechanisms and Functions

阐明淋巴细胞等位基因排除机制和功能

基本信息

  • 批准号:
    10466824
  • 负责人:
  • 金额:
    $ 44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-19 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Most T and B cells exhibit mono-allelic expression (allelic exclusion) of antigen receptor (AgR) genes. Although allelic exclusion was discovered in 1965, its underlying mechanisms and role(s) remain elusive. The initial and prevailing model for allelic exclusion is that expression of one type (specificity) of AgR inhibits autoimmunity by ensuring negative selection of cells with a self-reactive AgR. Consistent with this view, the expression of a second non-autoreactive AgR enables cells expressing a transgenic autoreactive AgR to evade negative selection. Yet, there remains a knowledge gap regarding effects of bi-allelic expression of endogenous TCRb, IgH, or Igk genes whose stringent allelic exclusion is achieved by mono-allelic initiation and feedback inhibition of V recombination. In addition to the likely benefit of mono-allelic expression, the applicant theorizes that mono-allelic AgR assembly suppresses oncogenic translocations from RAG endonuclease-generated DNA double strand breaks (DSBs). An obstacle to elucidating roles of allelic exclusion is the lack of a proven mechanism for mono-allelic initiation of V recombination. This has precluded experimental approaches to increase bi-allelic assembly and expression of AgR loci without otherwise altering V(D)J recombination, DSB responses, and/or lymphocyte development. Recombination signal sequences (RSSs) mediate V(D)J recombination by directing RAG activity. The applicant shows mice harboring replacement of Vb RSSs with a stronger RSS have substantially increased development of T cells with bi-allelic TCRb expression due to increased bi-allelic Vb recombination. Based on his preliminary data, the applicant hypothesizes that weak Vb and VH RSSs limit V recombination to restrict the incidence of V rearrangements on both alleles before feedback inhibition halts further V recombination. He hypothesizes that this stochastic mechanism of lowering V recombination frequency can be exploited to test roles of mono-allelic assembly and expression of TCRb, and possibly IgH, in immune homeostasis. He proposes two complementary but independent aims to test key aspects of these hypotheses. In Aim 1, the PI will use complementary in vitro biochemical and in vivo molecular assays to determine unequivocally whether inherently weak Vb and VH RSSs limit V recombination to enforce mono-allelic initiation of V recombination. In Aim 2, he will use Vb and VH RSS replacement mice to determine the impact of increasing bi-allelic assembly and expression of TCRb or IgH on negative selection of self-reactive cells, predisposition to autoimmunity, and genesis of oncogenic translocations. This project will show how RSSs control mono-allelic assembly and expression of TCRb, and identify if the same stochastic mechanism enforces IgH allelic exclusion. The data will, for the first time, demonstrate a mechanism for mono-allelic initiation of V recombination. The study has great potential to provide definitive evidence for a fundamental tenet of immunology proposed in 1965, but that remains unproven today. The work also may reveal an additional important benefit of mono-allelic initiation of V rearrangements in suppressing lymphoma.
摘要

项目成果

期刊论文数量(0)
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CRAIG H BASSING其他文献

CRAIG H BASSING的其他文献

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{{ truncateString('CRAIG H BASSING', 18)}}的其他基金

Elucidating Mechanisms of RAG Endonuclease Mediated Feedback Inhibition of V(D)J Recombination
阐明 RAG 核酸内切酶介导的 V(D)J 重组反馈抑制机制
  • 批准号:
    10538891
  • 财政年份:
    2022
  • 资助金额:
    $ 44万
  • 项目类别:
Exploring a Functional Role of Chromosome Loop Extrusion Direction on Regulating Genome Biology
探索染色体环挤出方向在调节基因组生物学中的功能作用
  • 批准号:
    10606672
  • 财政年份:
    2022
  • 资助金额:
    $ 44万
  • 项目类别:
Elucidating Mechanisms of RAG Endonuclease Mediated Feedback Inhibition of V(D)J Recombination
阐明 RAG 核酸内切酶介导的 V(D)J 重组反馈抑制机制
  • 批准号:
    10664014
  • 财政年份:
    2022
  • 资助金额:
    $ 44万
  • 项目类别:
Elucidating Lymphocyte Allelic Exclusion Mechanisms and Functions
阐明淋巴细胞等位排除机制和功能
  • 批准号:
    10684807
  • 财政年份:
    2019
  • 资助金额:
    $ 44万
  • 项目类别:
Elucidating Lymphocyte Allelic Exclusion Mechanisms and Functions
阐明淋巴细胞等位排除机制和功能
  • 批准号:
    10231184
  • 财政年份:
    2019
  • 资助金额:
    $ 44万
  • 项目类别:
Elucidating Lymphocyte Allelic Exclusion Mechanisms and Functions
阐明淋巴细胞等位基因排除机制和功能
  • 批准号:
    10020899
  • 财政年份:
    2019
  • 资助金额:
    $ 44万
  • 项目类别:
Elucidating Lymphocyte Allelic Exclusion Mechanisms and Functions
阐明淋巴细胞等位排除机制和功能
  • 批准号:
    9917182
  • 财政年份:
    2019
  • 资助金额:
    $ 44万
  • 项目类别:
Topological Control of Antigen Receptor Loci during Lymphocyte Development
淋巴细胞发育过程中抗原受体位点的拓扑控制
  • 批准号:
    10238038
  • 财政年份:
    2017
  • 资助金额:
    $ 44万
  • 项目类别:
Topological Control of Antigen Receptor Loci during Lymphocyte Development
淋巴细胞发育过程中抗原受体位点的拓扑控制
  • 批准号:
    9753111
  • 财政年份:
    2017
  • 资助金额:
    $ 44万
  • 项目类别:
Topological Control of Antigen Receptor Loci during Lymphocyte Development
淋巴细胞发育过程中抗原受体位点的拓扑控制
  • 批准号:
    9447778
  • 财政年份:
    2017
  • 资助金额:
    $ 44万
  • 项目类别:

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