IRF5-TNPO3 locus: Inclusion of TNPO3 as a unique regulator of IRF5 expression an

IRF5-TNPO3 基因座：将 TNPO3 作为 IRF5 表达的独特调节因子纳入其中

• 批准号: 9220283
• 负责人: Betsy J Barnes
• 金额: $ 17.49万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220283
• 关键词: IRF5; TNPO3; locus; Inclusion; unique

DESCRIPTION (provided by applicant): Project Summary The NIH estimates up to 23.5 million Americans suffer from autoimmune diseases and that the prevalence is rising; this statistic is higher than the number of Americans having cancer (9 million) or heart disease (22 million). Systemic lupus erythematosus (SLE) is the third most frequent autoimmune disease affecting approximately 1 in 2000 people. It is the prototype of complex autoimmune diseases and is characterized by extreme breakdown of self-tolerance resulting in multiple immunologic abnormalities. Cures are not yet available for SLE and patients face a lifetime of illness and treatment. Given the clinical heterogeneity of this disease, combined with limited knowledge of pathogenesis, designing new treatment options has been difficult. Recent findings from joint linkage and genome-wide association studies (GWAS) have provided significant insight into the genes and pathways contributing to disease pathogenesis. SLE is highly heritable with a strong genetic component that includes the interferon regulatory factor 5 (IRF5)-transportin 3 (TNPO3) region. Genetic variants in the IRF5-TNPO3 locus have been associated with SLE risk in every published study testing this region and in every ethnic population. Although some effort has recently gone into studying the functional consequence of genetic variants in IRF5, few studies have included an analysis of TNPO3 expression and function in SLE. The primary goal of this research proposal is to determine how the IRF5-TNPO3 locus alters SLE disease risk by experimentally bridging the gap(s) in knowledge between identification of this causal locus and its actual functional influence on SLE risk. IRF5 encodes a transcription factor central to the innate and adaptive immune response through its regulation of key processes including cytokine production, chemokine and chemokine receptor expression, and autoantibody production. TNPO3 is a member of the importin family and encodes a nuclear import receptor that mediates nuclear entry of serine/arginine (SR)-rich proteins such as splicing factors SFRS1 and SFRS2. Based on recent experimental findings from our lab, we hypothesize that the genetic risk coming from the IRF5-TNPO3 locus is not solely from IRF5 and directly involves TNPO3 function via its ability to regulate novel mechanisms controlling IRF5 alternative splicing and nuclear localization. This hypothesis will be tested in the following Specific Aims: 1) Determine the level of IRF5 and TNPO3 transcript and protein expression in immune cells from healthy donors and SLE patients carrying the risk and non-risk haplotypes at IRF5-TNPO3 SNPs, 2) Determine whether TNPO3 controls IRF5 transcript expression through its ability to regulate the import of SR proteins to the nucleus, and 3) Determine whether IRF5, TNPO3 and NUP62 differentially interact in genotyped healthy donor and SLE immune cells resulting in altered IRF5 nuclear localization. Results from this study will bridge the gap between disease- associated genetic variation, gene expression, protein function, and disease phenotype, and identify novel mechanisms that can be therapeutically targeted to regulate IRF5 expression and activation in SLE.

描述（由申请人提供）： 项目摘要NIH估计高达2350万美国人患有自身免疫性疾病，并且患病率正在上升。该统计数据高于患癌症（900万）或心脏病（2200万）的美国人人数。全身性红斑狼疮（SLE）是第三种经常出现的自身免疫性疾病，影响2000人约1人。它是复杂自身免疫性疾病的原型，其特征是自我耐受的极端分解，导致多种免疫学异常。 SLE尚未使用治疗方法，患者面临终生的疾病和治疗。鉴于该疾病的临床异质性，加上对发病机理有限的知识，设计新的治疗选择非常困难。联合联系和全基因组关联研究（GWAS）的最新发现为导致疾病发病机理的基因和途径提供了重大见解。 SLE具有强大的遗传成分，包括干扰素调节因子5（IRF5）-Transportin 3（TNPO3）区域。 IRF5-TNPO3基因座中的遗传变异与每项已发表的研究测试该地区和每个种族人口的SLE风险有关。尽管最近在研究IRF5中遗传变异的功能后果方面已经做出了一些努力，但很少有研究包括对SLE中TNPO3表达和功能的分析。该研究建议的主要目标是通过实验弥合该因果基因座的识别与其对SLE风险的实际功能影响之间的知识之间的知识来确定IRF5-TNPO3基因座如何改变SLE疾病风险。 IRF5通过调节包括细胞因子产生，趋化因子和趋化因子受体表达以及自身抗体产生的关键过程来编码具有先天和适应性免疫反应的转录因子。 TNPO3是Importin家族的成员，编码核进口受体，该核进口受体介导丝氨酸/精氨酸（SR） - 富含蛋白（例如剪接因子SFRS1和SFRS2）的核进口受体。根据我们实验室的最新实验发现，我们假设来自IRF5-TNPO3基因座的遗传风险不仅来自IRF5，并且直接涉及TNPO3功能，其能够调节控制IRF5替代拼接和核定位的新型机制。该假设将在以下特定目的中进行检验：1）确定来自健康供体的免疫细胞中IRF5和TNPO3转录物和蛋白质表达的水平，这些供体和SLE患者在IRF5-TNPO3 SNP上携带风险和非风险的单倍型，2） TNPO3和NUP62在基因分型健康供体和SLE免疫细胞中差异相互作用，从而改变IRF5核定位。这项研究的结果将弥合与疾病相关的遗传变异，基因表达，蛋白质功能和疾病表型之间的差距，并确定可以在SLE中调节IRF5表达和激活的新型机制。

项目成果

Interferon regulatory factor signaling in autoimmune disease.

• DOI: 10.1016/j.cyto.2017.02.006
• 发表时间: 2017-10
• 期刊: Cytokine
• 影响因子: 3.8
• 作者: Matta B;Song S;Li D;Barnes BJ
• 通讯作者: Barnes BJ

RNAi Transfection Optimized in Primary Naïve B Cells for the Targeted Analysis of Human Plasma Cell Differentiation.

在原代幼稚 B 细胞中优化 RNAi 转染，用于人浆细胞分化的靶向分析。

• DOI: 10.3389/fimmu.2019.01652
• 发表时间: 2019
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Shih,Tiffany;De,Saurav;Barnes,BetsyJ
• 通讯作者: Barnes,BetsyJ

Therapeutic Targeting of IRFs: Pathway-Dependence or Structure-Based?

• DOI: 10.3389/fimmu.2018.02622
• 发表时间: 2018-11-20
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Thompson，Cherrie D.;Matta，Bharati;Barnes，Betsy J.
• 通讯作者: Barnes，Betsy J.

The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.

• DOI: 10.1002/art.41953
• 发表时间: 2021-12
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Winkler A;Sun W;De S;Jiao A;Sharif MN;Symanowicz PT;Athale S;Shin JH;Wang J;Jacobson BA;Ramsey SJ;Dower K;Andreyeva T;Liu H;Hegen M;Homer BL;Brodfuehrer J;Tilley M;Gilbert SA;Danto SI;Beebe JJ;Barnes BJ;Pascual V;Lin LL;Kilty I;Fleming M;Rao VR
• 通讯作者: Rao VR