Interaction of environment and genetics in the predisposition to inflammatory art

环境和遗传学的相互作用导致炎症艺术的易感性

基本信息

  • 批准号:
    8974337
  • 负责人:
  • 金额:
    --
  • 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:
    2014-01-01 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Inflammatory arthritis is a highly debilitating and chronic immunological disease that results in pain and progressive destruction of the joints. Most arthritic syndromes are presumed polygenetic diseases with unknown etiologies. A prevailing theory is that in the context of genetic predisposition, environmental microbes trigger innate immunity in order to induce inflammatory disease. The preponderance of research to date has focused on adaptive and T cell responses in arthritis, with little being understood of what innate signals precede the activation of arthritis-causing T cells in the induction of disease. A recently identified gene NOD has unveiled important insight into the genetics involved in arthritis. A single base-pair change i NOD2 results in 100% penetrance of a disease called Blau syndrome wherein patients develop arthritis that is accompanied by inflammation of the eyes and skin. NOD2 belongs to the NOD-like receptor (NLR) family of pattern recognition receptors (PRRs) and is an important aspect of host defense against microbial pathogens, thereby suggesting an intriguing connection between microbial sensing and chronic inflammatory disease. To explore the role of NOD2 in arthritis, we chose to use disease modeled in the genetically susceptible SKG mouse strain because they develop a chronic, T cell-mediated arthritis that is induced by exposure to microbial triggers. In SKG mice, a spontaneous point mutation that perturbs T cell receptor signaling results in impaired positive and negative selection and enhanced production of autoreactive T cells. While arthritis in SKG mice is related to aberrant T cell responses, its initiation depends on innate immune mechanisms that activate the C- type lectin receptors (CLR), a class of PRRs known to be involved in host defense against fungal and mycobacterial infections. We crossed the NOD2 KO mice to the SKG mice and discovered that SKG mice deficient in NOD2 expression developed an exacerbated form of arthritis triggered by curdlan, which activates the CLR, Dectin-1. The three aims proposed relate to the hypothesis central of this application: NOD2 is an important determinant of arthritis susceptibility through regulation of immunological responses triggered by microbial activation of CLRs. We will: 1) Define how NOD2 expression influences the onset and development of arthritis triggered by curdlan in SKG mice, which includes how NOD2 expression influences inflammatory responses within the joint; 2) Elucidate the deleterious effects of NOD2-deficiency on arthritogenic T cell effector and regulatory responses that are involved in arthritis; 3) Determine whether the CARD9 pathway is essential for induction of arthritis in SKG mice and delineate the proximal CLRs central to arthritis regulated by NOD2 expression. That we have identified an innate immune receptor involved in a T cell- dependent disease may be an important clue into a powerful mechanism that has evolved to protect the joint from inflammation. Understanding the signaling mechanisms utilized by innate immune receptors such as CLRs and the effects of collaboration with NOD2, is an important question that needs to be addressed if the role of this receptor in arthritis is to be fuly understood. Results of the proposed studies delving into the mechanisms through which these innate immune pathways operate could open up new avenues for development of therapies for Blau syndrome and potentially also for other autoinflammatory, arthritic conditions.
描述(由申请人提供):

项目成果

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HOLLY Lallman ROSENZWEIG其他文献

HOLLY Lallman ROSENZWEIG的其他文献

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{{ truncateString('HOLLY Lallman ROSENZWEIG', 18)}}的其他基金

Back to Basics: T Cellular Control of Nod2 in Uveitis
回到基础:T 细胞对葡萄膜炎中 Nod2 的控制
  • 批准号:
    10615007
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Back to Basics: T Cellular Control of Nod2 in Uveitis
回到基础:T 细胞对葡萄膜炎中 Nod2 的控制
  • 批准号:
    10396089
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Monarch/NLRP12: A Newly discovered Innate Immune Receptor in Uveitis
Monarch/NLRP12:葡萄膜炎中新发现的先天免疫受体
  • 批准号:
    8969545
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Back to Basics: T Cellular Control of Nod2 in Uveitis
回到基础:T 细胞对葡萄膜炎中 Nod2 的控制
  • 批准号:
    10210400
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Innate Immunity and its integration in Autoimmune Disease of the Eye
先天免疫及其在眼自身免疫性疾病中的整合
  • 批准号:
    8860023
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Innate Immunity and its integration in Autoimmune Disease of the Eye
先天免疫及其在眼自身免疫性疾病中的整合
  • 批准号:
    9041596
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Interaction of environment and genetics in the predisposition to inflammatory art
环境和遗传学的相互作用导致炎症艺术的易感性
  • 批准号:
    8633790
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
NOD2 and Uveitis
NOD2 和葡萄膜炎
  • 批准号:
    8306860
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
NOD2 and Uveitis
NOD2 和葡萄膜炎
  • 批准号:
    8114023
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
NOD2 and Uveitis
NOD2 和葡萄膜炎
  • 批准号:
    7730112
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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