ABIN1 dysfunction in Lupus Nephritis

项目摘要 狼疮性肾炎(LN)是系统性红斑狼疮(SLE)常见而严重的并发症， 目前的治疗方法是有毒的，而且往往无效。狼疮性肾炎更常见，也更容易导致肾脏 非洲裔美国人患者中的失败[1-3]。系统性红斑狼疮有很强的遗传成分，但 非洲裔美国人对预后的遗传易感性知之甚少。先前的研究表明 TNIP1的变异与SLE和LN的易感性有关[4-7]。我们报告了与 一例大规模系统性红斑狼疮非裔美国人的TNIP1基因rs4958881与LN的多态性 基因分型研究[8]。我们的初步数据显示rs4958881变异与严重程度和 非裔美国人狼疮性肾炎的进展。TNIP1编码ABIN1蛋白，ABIN1具有生理功能 核因子-κB的抑制物，一种重要的免疫调节剂[9，10]。我们之前报道过分子的丢失 ABIN1在小鼠中的作用导致SLE样自身免疫和肾小球肾炎[8，11，12]。 虽然有证据表明，核因子-B的ABIN1调节在自身免疫和糖尿病的发生发展中发挥了作用。 事实上，知识中的一些关键差距仍然存在。首先，是什么分子机制调节了ABIN1- LN的相关性风险增加，它们是否针对不同的免疫细胞类型？第二，是否发生了变化 TNIP1基因多态性诱导的ABIN1功能在LN？第三，做TNIP1 比较多态在非裔美国人中具有不同的病理、分子和细胞效应 和美国白人在一起？ 为解决这些重要问题，提出了三个具体目标。目标1：比较协会 白种人和非裔美国人LN上的TNIP1变异体rs4958881。目标2：确定 TnIP1变异rs4958881对LN患者单核细胞、中性粒细胞和B细胞活性的影响。目标3.确定 ABIN1分子功能丧失改变单核细胞、中性粒细胞和B细胞功能的机制 使用ABIN1转基因小鼠。动物实验将与类似的 AIM 2中使用从具有TNIP1 rs4958881风险的LN患者血液中分离的相同细胞的实验 变种。 这是一个细胞和分子生物学家/生物化学家(David W.Powell博士)和一个 临床肾病学家/科学家(Dawn J.Caster博士)。这些调查人员已经发表了许多 关于LN中TINIP1/ABIN1功能的基因和动物研究报告现已确定 最近的初步研究结果评估了TNIP1基因多态在严重程度和 人类狼疮性肾炎的进展和特定的细胞和分子事件。翻译和人口- 这些研究的针对性将提供有影响力的见解，从而导致精确的诊断和 治疗高危非裔美国人LN患者。

Project Summary Lupus nephritis (LN) is a common and severe complication of systemic lupus erythematosus (SLE), and current therapies are toxic and frequently ineffective. LN is more prevalent and more likely to cause kidney failure in African American patients [1-3]. SLE has strong genetic components, but the relationship of genetic susceptibility to prognosis in African Americans is poorly understood. Previous studies showed variants of TNIP1 are associated with SLE and LN susceptibility [4-7]. We reported a strong association for the TNIP1 rs4958881 polymorphism with LN in African American patients from a large-scale SLE genotyping study [8]. Our preliminary data show an association of the rs4958881 variants with severity and progression of LN in African Americans. TNIP1 encodes the protein ABIN1 that functions as a physiological inhibitor of NF-κB, a prominent immune regulator [9, 10]. We reported previously that loss of the molecular function of ABIN1 in mice results in SLE-like autoimmunity and glomerulonephritis [8, 11, 12]. While there is evidence that ABIN1 regulation of NF-B plays a role in autoimmunity and development of LN, a number of critical gaps in knowledge remain. First, what molecular mechanisms mediate ABIN1- dependent enhanced risk of LN, and are they specific for different immune cell types? Second, does altered ABIN1 function induced by TNIP1 polymorphisms play a role in the racial disparity of LN? Third, do TNIP1 polymorphisms have different pathologic, molecular, and cellular effects in African Americans compared with White Americans? Three Specific Aims are proposed to address these significant questions. Aim 1: Compare the Association of theTNIP1 variant rs4958881 on LN in White and African Americans. Aim 2: Determine the effects of the TNIP1 variant rs4958881 on monocyte, neutrophils, and B cell activity in patients with LN. Aim 3. Determine the mechanisms by which loss of ABIN1 molecular function alters monocyte, neutrophil, and B cell function using ABIN1 transgenic mice. The animal experiments will be interpreted in conjunction with similar experiments in Aim 2 using the same cells isolated from blood of LN patients with the TNIP1 rs4958881 risk variant. This is a Multi-PI proposal with a Cell and Molecular Biologist/Biochemist (Dr. David W. Powell) and a Clinical Nephrologist/Scientist (Dr. Dawn J. Caster). These investigators have published many of the reports pertaining to TINIP1/ABIN1 function in LN via genetic and animal studies and are now poised with recent preliminary findings to evaluate causative roles for a TNIP1 polymorphism in severity and progression and specific cellular and molecular events in human LN. The translational and population- targeted nature of these studies will provide impactful insights that will lead to precision diagnostics and therapeutics for high-risk African American LN patients.