ABIN1 dysfunction in Lupus Nephritis

狼疮性肾炎中的 ABIN1 功能障碍

基本信息

批准号：
10675771
负责人：
Dawn Caster
金额：
$ 58.4万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675771
关键词：
Address African American African American population Alleles Animal Experiments Animals Autoimmunity B-Lymphocytes Binding Proteins Biological Response Modifiers Blood Bone Marrow CXCL10 gene CXCR3 gene Cell Maturation Cell Separation Cell physiology Cells Clinical Complication Data Development Diffuse Disease Disease Outcome Event Functional disorder Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genotype Glomerulonephritis Human Immune Immune Complex Glomerulonephritis Inflammation Mediators Inflammatory Interleukin-6 Investigation Kidney Kidney Failure Knowledge Lupus Nephritis Mature T-Lymphocyte Mediating Molecular Mus Mutation Nature Nuclear Outcome Pathologic Patients Peripheral Physiological Polyubiquitin Precision therapeutics Predisposition Production Prognosis Proteins Proteinuria Publishing Race Regulation Reporting Research Personnel Risk Role Sampling Scientist Serum Severities Severity of illness Systemic Lupus Erythematosus T-Lymphocyte TNF gene Target Populations Transcriptional Regulation Transgenic Mice Transgenic Organisms Transplantation Validation Variant Wild Type Mouse anti-dsDNA autoantibody caucasian American cell type chemokine cohort cytokine diagnostic biomarker disorder risk experimental study genetic variant high risk inhibitor insight monocyte neutrophil novel diagnostics personalized diagnostics podocyte protein function racial disparity risk variant therapeutic target

项目摘要

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.

项目摘要狼疮肾炎（LN）是全身性红斑狼疮（SLE）的常见且严重的并发症，当前的疗法有毒且经常无效。 LN更普遍，更可能引起肾脏非裔美国人患者失败[1-3]。 SLE具有强大的遗传成分，但是对非裔美国人预后的遗传敏感性知之甚少。先前的研究显示 TNIP1的变体与SLE和LN敏感性相关[4-7]。我们报道了强烈的关联来自大规模SLE的非裔美国人患者的TNIP1 RS4958881多态性基因分型研究[8]。我们的初步数据显示了RS4958881变体与严重性和非裔美国人的LN进展。 TNIP1编码起作用的蛋白质Abin1 NF-κB的抑制剂，一种突出的免疫调节剂[9，10]。我们先前报道了分子的损失 ABIN1在小鼠中的功能会导致SLE样自身免疫性和肾小球肾炎[8，11，12]。虽然有证据表明，ABIN1对NF-B的调节在自身免疫和发展中起作用 LN，仍然存在许多关键差距。首先，哪些分子机制介导abin1-- 依赖性LN风险增强，并且它们是否针对不同的免疫细胞类型？其次，确实改变了 TNIP1多态性引起的ABIN1功能在LN的种族差异中起作用？第三，做TNIP1 多态性在非裔美国人中具有不同的病理，分子和细胞作用与白人美国人？提出了三个具体目标来解决这些重大问题。目标1：比较协会白人和非裔美国人的LN上的TNIP1变体rs4958881。目标2：确定 LN患者的单核细胞，中性粒细胞和B细胞活性的TNIP1变体RS4958881。目标3。确定 abin1分子功能丧失的机制改变了单核细胞，中性粒细胞和B细胞功能使用Abin1转基因小鼠。动物实验将与类似的解释在AIM 2中使用与TNIP1 rs4958881风险的LN血液中的相同细胞进行的实验变体。这是一个具有细胞和分子生物学家/生物化学家（David W. Powell博士）和A的多PI建议临床肾脏科学家/科学家（Dawn J. Caster博士）。这些调查人员发表了许多通过遗传和动物研究与LN中TINIP1/ABIN1功能有关的报告，现在被中毒最近的初步发现，用于评估TNIP1多态性在严重程度和人类LN中的进展以及特定的细胞和分子事件。翻译和人口 - 这些研究的针对性性质将提供有影响力的见解，从而导致精确诊断和高危非裔美国人LN患者的治疗疗法。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Focus Group Study of Self-Management in Patients With Glomerular Disease.

DOI：
10.1016/j.ekir.2021.10.011
发表时间：
2022-01
期刊：
Kidney international reports
影响因子：
6
作者：
Carter SA;Teng C;Gutman T;Logeman C;Cattran D;Lightstone L;Bagga A;Barbour SJ;Barratt J;Boletis J;Caster DJ;Coppo R;Fervenza FC;Floege J;Hladunewich MA;Hogan JJ;Kitching AR;Lafayette RA;Malvar A;Radhakrishnan J;Rovin BH;Scholes-Robertson N;Trimarchi H;Zhang H;Azukaitis K;Cho Y;Viecelli AK;Dunn L;Harris D;Johnson DW;Kerr PG;Laboi P;Ryan J;Shen JI;Ruiz L;Wang AY;Lee AHK;Ka Shun SF;Ka-Hang Tong M;Teixeira-Pinto A;Wilkie M;Alexander SI;Craig JC;Martin A;Tong A
通讯作者：
Tong A

Management of Lupus Nephritis: New Treatments and Updated Guidelines.