Functional insights into the IRF5 genetic variants marking SLE risk.

对标记 SLE 风险的 IRF5 遗传变异的功能见解。

• 批准号: 8968765
• 负责人: Ram Savan
• 金额: $ 24.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968765
• 关键词: Address; Adrenal Cortex Hormones; Amino Acids; Autoimmune Diseases; Autoimmunity; Biochemical; Biological; Cells; Data; Dendritic Cells; Development; Exons; Family; Gender; Genes; Genetic; Genetic Polymorphism; Glutamic Acid; Goals; Haplotypes; Immune; Individual; Interferon Activation; Interferon Type I; Interferons; Lupus; Molecular; Molecular Conformation; Patients; Pharmaceutical Preparations; Predisposition; Production; Proline; RNA Splicing; Race; Regulation; Research; Research Proposals; Risk; Role; Serine; Signal Pathway; Signal Transduction; Systemic Lupus Erythematosus; Threonine; Translating; Variant; base; drug development; gene induction; genetic association; genetic variant; genome wide association study; high risk; immune activation; insertion/deletion mutation; insight; protein function; public health relevance; risk variant; transcription factor

 DESCRIPTION (provided by applicant): The goal of the proposed research is to determine how the interferon regulatory factor 5(IRF5) lupus risk variant translates into biological risk of systemic lupus erythematosus (SLE). Genome wide association studies (GWAS) have identified IRF5 as one of the most strongly associated genes with susceptibility to SLE. Although the genetic association of IRF5 with lupus is clear, the exact mechanism by which IRF5 risk variant promotes susceptibility for lupus is still unknown. We hypothesize that IRF8 could be a negative regulatory factor of IRF5 activity under normal conditions, while in lupus the IRF5 exon 6 risk variants are capable of escaping this negative regulation thereby activating type I IFNs leading to aberrant immune activation. To address this question, we will (SA1) characterize IRF5 exon 6 variants in pDCs using molecular and biochemical approaches, (SA2) investigate the effects of IRF8 on IRF5 exon 6 variants, and (SA3) effect of IRF5 exon 6 variation on IRF5 activation in SLE patients. If IRF8 blocks IRF5 activation, this will be a significant step to gain the mechanistic understanding of aberrant production type I IFNs and immune activation in lupus.

 描述(由申请人提供)：拟议研究的目标是确定干扰素调节因子5(IRF5)狼疮风险变体如何转化为系统性红斑狼疮(SLE)的生物学风险。全基因组关联研究发现，IRF5基因是与SLE易感性最强的基因之一。虽然IRF5与狼疮的遗传关联是明确的，但IRF5风险变异促进狼疮易感性的确切机制仍不清楚。我们推测，在正常情况下，IRF8可能是IRF5活性的负调控因子，而在狼疮中，IRF5外显子6风险变异体能够逃避这种负调控，从而激活I型IFN，导致异常的免疫激活。为了解决这个问题，我们将(SA1)用分子和生化方法鉴定pDC中的IRF5外显子6变异，(SA2)研究IRF8对IRF5外显子6变异的影响，以及(SA3)IRF5外显子6变异对SLE患者IRF5激活的影响。如果IRF8阻断IRF5的激活，这将是了解狼疮I型IFN异常产生和免疫激活机制的重要一步。