Contributions of autophagy-related genes in lupus

自噬相关基因在狼疮中的贡献

基本信息

  • 批准号:
    10682136
  • 负责人:
  • 金额:
    $ 75.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-18 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Lupus or systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease with a substantial genetic basis. SLE is characterized by abnormal T- and B-cell responses, production of numerous pathogenic autoantibodies, and immune complex deposition, leading to various clinical manifestations including multi-organ damage (e.g., kidneys, skin). SLE has disproportionate impacts based on gender and ethnicity. Approximately 90% of those affected are women. In addition, SLE has a 3-5-fold higher prevalence in Asian, African-American, and Hispanic individuals compared to those with European ancestry, as well as more severe clinical manifesta- tions, including organ damage (e.g., nephritis). Evidence from genetics, cell biology, and animal models suggests that autophagy, a major pathway for organelle and protein turnover, plays a pivotal role in SLE pathogenesis. Autophagy is a highly conserved lysosome-mediated catabolic process that removes unwanted cytoplasmic components (e.g., long-lived and/or misfolded proteins) and damaged organelles. This process maintains cellular homeostasis and survival under metabolic stress. Recent genome-wide association studies (GWAS) have linked autoimmune diseases, including SLE, to autophagy-related genes. However, there is currently a huge gap in defining causal relationships between associated variants and molecular mechanisms underlying SLE. This lack of knowledge about pathogenic effects underlying GWAS signals hinders translating GWAS discoveries into diagnosis and treatment. To address this issue, we selected six highly ranked, well-replicated loci; four of them were initially discovered in Asian populations, two we previously reported as novel loci for SLE susceptibility. We have assembled a research team with the expertise and resources to discover and mechanistically characterize functional variants linked to SLE. We hypothesize that at each GWAS locus, both common and rare variants contribute to SLE risk by affecting expression of autophagy genes through tissue-specific regulatory elements. Aim 1 will identify SLE-predisposing variants using a comprehensive imputation-based analysis of combined novel resequencing data from SLE patients and controls in addition to our previous fine-mapping of four ethnically diverse populations. Functional variants will be prioritized by allele-specific expression, open chromatin, and 3D interaction data from immune cells. We will elucidate genetic and clinical heterogeneity of SLE by assessing association of identified variants with SLE and its clinical manifestations and autoantibody profiles. Associated variants, especially imputed and rare variants, will be validated through follow-up genotyping. Aim 2 will define the mechanistic and functional consequences of SLE-predisposing variants using appropriate functional assays, including CRISPR-based gene knock-out and base-editing in cell lines (Jurkat, Toledo, podocyte, HEK293) and primary immune cells (T- and B-cells) relevant to SLE. Thus, we will uncover functional variants underlying SLE association signals, and illuminate mechanisms by which these variants contribute to lupus and its clinical manifestations. Through this approach, our analysis should yield novel targets for potential clinical interventions.
摘要

项目成果

期刊论文数量(0)
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Swapan K. Nath其他文献

Genetic epidemiology of vitiligo: multilocus recessivity cross-validated.
白癜风的遗传流行病学:多位点隐性交叉验证。
  • DOI:
  • 发表时间:
    1994
  • 期刊:
  • 影响因子:
    9.8
  • 作者:
    Swapan K. Nath;Partha P. Majumder;James J. Nordlund
  • 通讯作者:
    James J. Nordlund
potential for generating B cells with a diverse immunoglobulin repertoire Human fetal, cord blood, and adult lymphocyte progenitors have similar
产生具有多种免疫球蛋白库的 B 细胞的潜力 人类胎儿、脐带血和成人淋巴细胞祖细胞具有相似的特性
  • DOI:
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Grant R. Kolar;Takafumi Yokota;Maria Isabel D. Rossi;Swapan K. Nath;J. D. Capra
  • 通讯作者:
    J. D. Capra

Swapan K. Nath的其他文献

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{{ truncateString('Swapan K. Nath', 18)}}的其他基金

Connecting the gap between GWAS and functional targets for lupus susceptibility
连接 GWAS 和狼疮易感性功能目标之间的差距
  • 批准号:
    10618360
  • 财政年份:
    2022
  • 资助金额:
    $ 75.26万
  • 项目类别:
Connecting the gap between GWAS and functional targets for lupus susceptibility
连接 GWAS 和狼疮易感性功能目标之间的差距
  • 批准号:
    10433444
  • 财政年份:
    2022
  • 资助金额:
    $ 75.26万
  • 项目类别:
Role of Two Interferon Regulatory Genes in Lupus
两个干扰素调节基因在狼疮中的作用
  • 批准号:
    9895394
  • 财政年份:
    2020
  • 资助金额:
    $ 75.26万
  • 项目类别:
Role of Two Interferon Regulatory Genes in Lupus
两个干扰素调节基因在狼疮中的作用
  • 批准号:
    10115587
  • 财政年份:
    2020
  • 资助金额:
    $ 75.26万
  • 项目类别:
Localizing functional variants in SLE susceptibility genes
定位 SLE 易感基因的功能变异
  • 批准号:
    8995183
  • 财政年份:
    2015
  • 资助金额:
    $ 75.26万
  • 项目类别:
Localizing functional variants in SLE susceptibility genes
定位 SLE 易感基因的功能变异
  • 批准号:
    8823171
  • 财政年份:
    2015
  • 资助金额:
    $ 75.26万
  • 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
  • 批准号:
    9259737
  • 财政年份:
    2014
  • 资助金额:
    $ 75.26万
  • 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
  • 批准号:
    8776043
  • 财政年份:
    2014
  • 资助金额:
    $ 75.26万
  • 项目类别:
Health Disparities and Genetic Architecture of Lupus in African Americans
非裔美国人的健康差异和狼疮的遗传结构
  • 批准号:
    9053279
  • 财政年份:
    2014
  • 资助金额:
    $ 75.26万
  • 项目类别:
NADPH-Oxidase and SLE Susceptibility
NADPH 氧化酶和 SLE 易感性
  • 批准号:
    8651414
  • 财政年份:
    2013
  • 资助金额:
    $ 75.26万
  • 项目类别:

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