Complement in the Pathogenesis of Autoimmune Arthritis

补体在自身免疫性关节炎发病机制中的作用

基本信息

  • 批准号:
    10255878
  • 负责人:
  • 金额:
    $ 34.21万
  • 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:
    2020-09-23 至 2021-02-18
  • 项目状态:
    已结题

项目摘要

The complement system is a major pro-inflammatory and immunomodulatory pathway and plays a central role in the mechanisms that drive the pathogenesis of experimental murine models of human rheumatoid arthritis (RA). In these murine models, inappropriate complement activation that is directed to self-tissues drives initial cellular influx into the joint as well as synovial inflammation and bone erosions. However, despite the extensive insights into the murine disease that we have developed with support of this grant, including the activation pathways involved, how control of the system is overcome and how individual effector pathways promote tissue damage, we do not know how the complement system plays a pathogenic role in patients with RA. Recent findings in our studies of the human disease have identified a prolonged preclinical phase in RA characterized by the presence of circulating autoantibodies and mucosal inflammation that appears to drive the initial break in tolerance to citrullinated self-antigens. Following that asymptomatic phase, where complement activation is present in the mucosal site but not systemically, it is likely that complement activation and effector mechanisms are then especially important as the disease transitions to the very early phases of synovitis when circulating autoantibodies directed against citrullinated proteins initially react with antigens which develop and are displayed in the joint. To build our understanding of the human disease and translate information from models of disease to patients themselves, the major focus of this competing renewal proposal is to understand how the complement system is involved in the early synovitis in RA. We are especially well positioned to accomplish this important goal, as with other support mechanisms we are able to identify and follow subjects from the preclinical period into the very first appearance of synovitis and the diagnosis of RA. By obtaining synovial biopsies, a skill set also developed in our program in the last 3-4 years through other funding, and informative blood samples from patients in this important transition period, we will work to characterize the role of complement activation as well as its regulatory and effector mechanisms in the initial development of inflammatory arthritis and synovitis in patients. In addition, as there are distinct sub-types of RA, designated pathotypes, which have prognostic importance, we will determine what complement activation processes are associated with individual pathotypes. Finally, we will focus special attention on a major synovial cell type in human RA, which are highly inflammatory fibroblast-like synoviocytes, whose importance is increasingly understood and for which there are reported complement signatures in unbiased omics studies. We will define the mechanisms by which complement interacts with this cell type, both with regard to how complement is activated as well as defining the phenotypic changes in these cells following activation. A major goal in these studies is to use information gained to inform the use of current and next generation complement therapeutics in this important human autoimmune disease.
补体系统是一个主要的促炎和免疫调节途径,并发挥核心作用

项目成果

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会议论文数量(0)
专利数量(0)

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Vernon Michael Holers其他文献

Vernon Michael Holers的其他文献

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{{ truncateString('Vernon Michael Holers', 18)}}的其他基金

Center for Mucosal Immunobiology and Rheumatic Disease Pathogenesis
粘膜免疫生物学和风湿病发病机制中心
  • 批准号:
    10277290
  • 财政年份:
    2021
  • 资助金额:
    $ 34.21万
  • 项目类别:
Center for Mucosal Immunobiology and Rheumatic Disease Pathogenesis Administrative Core
粘膜免疫生物学和风湿性疾病发病机制中心行政核心
  • 批准号:
    10277291
  • 财政年份:
    2021
  • 资助金额:
    $ 34.21万
  • 项目类别:
Center for Mucosal Immunobiology and Rheumatic Disease Pathogenesis
粘膜免疫生物学和风湿病发病机制中心
  • 批准号:
    10700077
  • 财政年份:
    2021
  • 资助金额:
    $ 34.21万
  • 项目类别:
Center for Mucosal Immunobiology and Rheumatic Disease Pathogenesis Administrative Core
粘膜免疫生物学和风湿性疾病发病机制中心行政核心
  • 批准号:
    10700078
  • 财政年份:
    2021
  • 资助金额:
    $ 34.21万
  • 项目类别:
Novel Therapeutic Approaches for Lupus Nephritis
狼疮性肾炎的新治疗方法
  • 批准号:
    10190935
  • 财政年份:
    2020
  • 资助金额:
    $ 34.21万
  • 项目类别:
Novel Therapeutic Approaches for Lupus Nephritis
狼疮性肾炎的新治疗方法
  • 批准号:
    10615186
  • 财政年份:
    2020
  • 资助金额:
    $ 34.21万
  • 项目类别:
Novel Therapeutic Approaches for Lupus Nephritis
狼疮性肾炎的新治疗方法
  • 批准号:
    10403435
  • 财政年份:
    2020
  • 资助金额:
    $ 34.21万
  • 项目类别:
Novel Therapeutic Approaches for Lupus Nephritis
狼疮性肾炎的新治疗方法
  • 批准号:
    10033331
  • 财政年份:
    2020
  • 资助金额:
    $ 34.21万
  • 项目类别:
Complement in the Pathogenesis of Autoimmune Arthritis
补体在自身免疫性关节炎发病机制中的作用
  • 批准号:
    9044728
  • 财政年份:
    2015
  • 资助金额:
    $ 34.21万
  • 项目类别:
Evolving Adaptive and Effector Mechanisms from Pre-RA through Established Disease
从 RA 前期到已确定疾病的适应性和效应机制的演变
  • 批准号:
    9323969
  • 财政年份:
    2014
  • 资助金额:
    $ 34.21万
  • 项目类别:

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