Role of the transcription factor Ikaros in development of autoimmune disease

转录因子 Ikaros 在自身免疫性疾病发展中的作用

基本信息

  • 批准号:
    10408036
  • 负责人:
  • 金额:
    $ 39.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-06-15 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Autoimmune diseases are chronic and often disabling illnesses that affect millions of Americans. Current treatments help to prevent the symptoms of autoimmune disease, but there are no cures. Autoimmune disease is thought to be due to a combination of genetic predispositions and environmental factors, but the etiology is not fully understood. In order to develop new and improved treatments, and to potentially find a cure, a better understanding of the underlying molecular mechanisms of autoimmune disease is essential. Using a newly established strain of mutant mice, we found that a small targeted deletion in the gene encoding the transcription factor Ikaros, resulted in a profound defect in immune tolerance, with high levels of autoreactive antibodies in the serum of very young mice. Antibodies are produced by B cells, and the presence of autoreactive antibodies indicates that Ikaros is necessary to control how B cells respond to antigen and to ensure tolerance to self. A role for Ikaros in human autoimmune disease is supported by recent genome-wide association studies (GWAS), where genetic variants in the Ikaros gene locus (IKZF1) have been linked to several autoimmune diseases. Furthermore, recent studies have reported patients with autoimmune disease that carry IKZF1 mutations. We propose to employ our Ikaros-mutant mice as a new model of autoimmunity to investigate the molecular mechanisms underlying the break of tolerance in Ikaros-mutated B cells. We have preliminary data suggesting that Ikaros regulates two distinct stages of B-cell maturation that are critical for proper tolerance: The central tolerance checkpoint and the requirement for costimulatory signal upon Ag encounter in the periphery. We will use this mouse model to directly test the hypothesis that Ikaros limits autoreactive B cells by enforcing central tolerance and establishing a requirement for the “second signal” (indicating danger) through epigenetic mechanisms. Accordingly, our study design is focused on an understanding of central tolerance and B-cell autoreactivity, using a combination of in vivo and ex vivo approaches. to directly assess the gene expression, epigenetic and signaling pathways associated with proper versus aberrant B cell activation. Specifically, we will investigate the role of Ikaros in BCR signaling and establishment of central tolerance (Aim 1). We will employ our Ikaros-mutant model to investigate the role of Ikaros in the molecular mechanisms regulating mature B-cell response to antigen (Aim 2). Lastly, we will examine the B-cell intrinsic, as well as the relative extrinsic contributions and roles of different immune cell lineages in the observed break of B-cell tolerance (Aim 3).
摘要

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
ssvQC: an integrated CUT&RUN quality control workflow for histone modifications and transcription factors.
  • DOI:
    10.1186/s13104-021-05781-8
  • 发表时间:
    2021-09-20
  • 期刊:
  • 影响因子:
    1.8
  • 作者:
    Boyd J;Rodriguez P;Schjerven H;Frietze S
  • 通讯作者:
    Frietze S
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Seth E Frietze其他文献

Seth E Frietze的其他文献

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{{ truncateString('Seth E Frietze', 18)}}的其他基金

Project 2: Bromodomains as Epigenetic Modulators of Endocrine Responsiveness in ER+ Breast Cancer
项目 2:溴结构域作为 ER 乳腺癌内分泌反应性的表观遗传调节剂
  • 批准号:
    10608056
  • 财政年份:
    2021
  • 资助金额:
    $ 39.54万
  • 项目类别:
Project 2: Bromodomains as Epigenetic Modulators of Endocrine Responsiveness in ER+ Breast Cancer
项目 2:溴结构域作为 ER 乳腺癌内分泌反应性的表观遗传调节剂
  • 批准号:
    10380072
  • 财政年份:
    2021
  • 资助金额:
    $ 39.54万
  • 项目类别:
Deciphering the molecular mechanisms of histone code recognition by ATAD2/B
破译 ATAD2/B 组蛋白密码识别的分子机制
  • 批准号:
    10410677
  • 财政年份:
    2018
  • 资助金额:
    $ 39.54万
  • 项目类别:
Understanding Ikaros molecular functions for targeted therapies of pre-B ALL
了解 Ikaros 分子功能用于前 B ALL 靶向治疗
  • 批准号:
    10433981
  • 财政年份:
    2018
  • 资助金额:
    $ 39.54万
  • 项目类别:
Role of the transcription factor Ikaros in development of autoimmune disease
转录因子 Ikaros 在自身免疫性疾病发展中的作用
  • 批准号:
    10159202
  • 财政年份:
    2018
  • 资助金额:
    $ 39.54万
  • 项目类别:
Deciphering the molecular mechanisms of histone code recognition by ATAD2/B
破译 ATAD2/B 组蛋白密码识别的分子机制
  • 批准号:
    9788498
  • 财政年份:
    2018
  • 资助金额:
    $ 39.54万
  • 项目类别:
Deciphering the molecular mechanisms of histone code recognition by ATAD2/B
破译 ATAD2/B 组蛋白密码识别的分子机制
  • 批准号:
    10005379
  • 财政年份:
    2018
  • 资助金额:
    $ 39.54万
  • 项目类别:
Deciphering the molecular mechanisms of histone code recognition by ATAD2/B
破译 ATAD2/B 组蛋白密码识别的分子机制
  • 批准号:
    10592912
  • 财政年份:
    2018
  • 资助金额:
    $ 39.54万
  • 项目类别:
Understanding Ikaros molecular functions for targeted therapies of pre-B ALL
了解 Ikaros 分子功能用于前 B ALL 靶向治疗
  • 批准号:
    10203874
  • 财政年份:
    2018
  • 资助金额:
    $ 39.54万
  • 项目类别:
Deciphering the molecular mechanisms of histone code recognition by ATAD2/B
破译 ATAD2/B 组蛋白密码识别的分子机制
  • 批准号:
    10452326
  • 财政年份:
    2018
  • 资助金额:
    $ 39.54万
  • 项目类别:

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