Autoimmunity risk alleles compromising B cell anergy

损害 B 细胞无反应性的自身免疫风险等位基因

基本信息

  • 批准号:
    9121221
  • 负责人:
  • 金额:
    $ 45.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-03-01 至 2021-02-28
  • 项目状态:
    已结题

项目摘要

Autoimmunity is caused by conspiring effects of genetic predisposition and environmental factors such as injury, infection and microbiome constitution. While multiple genetic loci affect susceptibility, in most cases each in isolation has only a small effect, suggesting that disease develops only when multiple risk-conferring alleles that function in concert are inherited by a single individual. We hypothesize that such a situation exists in autoreactive B cells where multiple SLE risk alleles encode molecules that appear to function in signaling pathways that function normally to limit/terminate antigen receptor signaling. In this application we propose to test this hypothesis, analyzing the functional interplay of this set of genes/protein and their risk conferring alleles. Future development and implementation of “precision” medical approaches for treatment of autoimmunity will require an understanding of the mechanisms by which genetic variations conspire to increase disease risk, and research proposed here represents a critical first step to enable these efforts. A number of autoimmunity risk alleles encode molecules previously proposed to function as intermediaries in signaling pathways involved in regulation of B cell activation. As such they may be important in keeping autoreactive B cells from becoming activated and contributing to autoimmunity. In this application we request support to define the functions and functional interactions of proteins encoded by six genes, variants of which confer increased risk of autoimmunity. Previous reports indicate that B cell-targeted deletion of genes encoding SHIP-1, PTEN, SHP-1 or LYN, expression of PTPN22 (PEP-R619W), or increased expression of CSK, promote the development of autoimmunity. However the mechanism by which this occurs is unknown. We hypothesize that these proteins function as intermediaries in a bifurcating pathway in which final effectors are the inositol lipid phosphatases SHIP-1 and the tyrosine phosphatase SHP-1. Further, we suggest that both terminal effectors are required for maintenance of antigen unresponsiveness of anergic B cells. The studies will employ reductionist genetic models in which risk allele mimetic changes in expression/function of the proteins can be induced acutely in anergic B cells, and subsequent cell activation, proliferation, differentiation and autoantibody production monitored. Aim 1 will test the hypothesis that PTPN22, CSK and LYN act in linear pathways upstream of SHIP-1 and SHP-1, and that genetic variations that confer risk compromise anergy by undermining their regulatory function. Aim 2 will define the downstream consequences of acute introduction of risk allele mimetic conditions in terms of development of autoimmune disease, and will test candidate therapeutic kinase inhibitors. Aim 3 will translate findings, examining the role of SHIP-1 and SHP-1 phosphatases in maintenance anergy of human B cells. Proposed studies will provide important new insight regarding the in vivo lifestyle of autoreactive B cells whose anergy is compromised by autoimmunity risk alleles.
自身免疫是由遗传易感性和环境因素的共同作用引起的, 损伤、感染和微生物组构成。虽然多个遗传位点影响易感性,但在大多数情况下, 每一种单独的作用都很小,这表明疾病只有在多种风险因素共同作用下才会发展。 协同作用的等位基因由单个个体遗传。我们假设这样的情况存在 在自身反应性B细胞中,多个SLE风险等位基因编码似乎在信号传导中起作用的分子, 正常发挥功能以限制/终止抗原受体信号传导的途径。在本申请中,我们提出 测试这一假设,分析这组基因/蛋白质的功能相互作用及其风险赋予 等位基因未来发展和实施“精确”医疗方法治疗 自身免疫需要了解遗传变异的机制, 增加疾病风险,这里提出的研究是实现这些努力的关键第一步。 许多自身免疫风险等位基因编码先前提出的在免疫调节中起中介作用的分子。 参与调节B细胞活化的信号通路。因此,他们可能是重要的, 自身反应性B细胞被激活并导致自身免疫。在本申请中,我们要求 支持定义由六个基因编码的蛋白质的功能和功能相互作用,其中 增加自身免疫的风险。先前的报道表明,B细胞靶向缺失编码 SHIP-1、PTEN、SHP-1或林恩、PTPN 22(PEP-R619 W)的表达或CSK的表达增加, 促进自身免疫的发展。然而,这种情况发生的机制尚不清楚。我们 假设这些蛋白质在最终效应物被 肌醇脂质磷酸酶SHIP-1和酪氨酸磷酸酶SHP-1。此外,我们建议双方 维持无反应性B细胞的抗原无反应性需要末端效应物。这些研究将 采用简化的遗传模型,其中风险等位基因模拟蛋白质表达/功能的变化 可在无反应性B细胞中急性诱导,随后的细胞活化、增殖、分化和 监测自身抗体产生。目的1将检验PTPN 22、CSK和林恩以线性方式起作用的假设。 SHIP-1和SHP-1上游通路,以及赋予风险的遗传变异通过以下方式损害无反应性: 削弱其监管功能。目标2将定义急性引入 在自身免疫性疾病的发展方面具有风险等位基因模拟条件,并将测试候选人 治疗性激酶抑制剂。目标3将翻译研究结果,检查SHIP-1和SHP-1的作用 磷酸酶在维持人B细胞无反应性中的作用拟议的研究将提供重要的新见解 关于自身反应性B细胞的体内生活方式,其无反应性受到自身免疫风险等位基因的损害。

项目成果

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

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

John C Cambier其他文献

Src-family kinases in B-cell development and signaling
B 细胞发育和信号转导中的 Src 家族激酶
  • DOI:
    10.1038/sj.onc.1208075
  • 发表时间:
    2004-10-18
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Stephen B Gauld;John C Cambier
  • 通讯作者:
    John C Cambier

John C Cambier的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('John C Cambier', 18)}}的其他基金

Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
  • 批准号:
    9568080
  • 财政年份:
    2016
  • 资助金额:
    $ 45.51万
  • 项目类别:
Insulin Specific T and B cells in Type 1 Diabetes
1 型糖尿病中的胰岛素特异性 T 细胞和 B 细胞
  • 批准号:
    9180031
  • 财政年份:
    2016
  • 资助金额:
    $ 45.51万
  • 项目类别:
Perturbation of B cell anergy in T1D
T1D 中 B 细胞无反应性的扰动
  • 批准号:
    9225164
  • 财政年份:
    2016
  • 资助金额:
    $ 45.51万
  • 项目类别:
Perturbation of B cell anergy in T1D
T1D 中 B 细胞无反应性的扰动
  • 批准号:
    9121223
  • 财政年份:
    2016
  • 资助金额:
    $ 45.51万
  • 项目类别:
B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
  • 批准号:
    8372067
  • 财政年份:
    2012
  • 资助金额:
    $ 45.51万
  • 项目类别:
B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
  • 批准号:
    9104150
  • 财政年份:
    2012
  • 资助金额:
    $ 45.51万
  • 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
  • 批准号:
    8282484
  • 财政年份:
    2012
  • 资助金额:
    $ 45.51万
  • 项目类别:
B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
  • 批准号:
    8690052
  • 财政年份:
    2012
  • 资助金额:
    $ 45.51万
  • 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
  • 批准号:
    8519291
  • 财政年份:
    2012
  • 资助金额:
    $ 45.51万
  • 项目类别:
B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
  • 批准号:
    8534115
  • 财政年份:
    2012
  • 资助金额:
    $ 45.51万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 45.51万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了