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.

项目概要狼疮性肾炎 (LN) 是系统性红斑狼疮 (SLE) 常见且严重的并发症，目前的治疗方法有毒且常常无效，LN 更为普遍，并且更有可能导致肾病。非裔美国患者的失败与遗传因素密切相关[1-3]。先前的研究表明，对非裔美国人预后的遗传易感性知之甚少。 TNIP1 的变异与 SLE 和 LN 易感性相关 [4-7]。患有大规模 SLE 的非洲裔美国患者中 TNIP1 rs4958881 多态性与 LN 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 TNIP1 编码蛋白质 ABIN1，具有生理功能。 NF-κB 抑制剂，一种重要的免疫调节剂 [9, 10] 我们之前报道过该分子的丢失。 ABIN1 在小鼠中的功能会导致 SLE 样自身免疫和肾小球肾炎 [8,11,12]。虽然有证据表明 ABIN1 对 NF-κB 的调节在自身免疫和发育中发挥作用 LN，知识方面仍然存在一些关键差距，首先，什么分子机制介导 ABIN1-。 LN 的依赖性增强风险，它们对不同的免疫细胞类型是否具有特异性？ TNIP1 多态性诱导的 ABIN1 功能在 LN 的种族差异中发挥作用吗？与非洲裔美国人相比，多态性具有不同的病理、分子和细胞效应与美国白人？提出了三个具体目标来解决这些重要问题。目标 1：比较协会。目的 2：确定 TNIP1 变体 rs4958881 对 LN 的影响。 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。 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转基因小鼠的动物实验将结合类似的实验进行解释。目标 2 中的实验使用从具有 TNIP1 rs4958881 风险的 LN 患者血液中分离出的相同细胞变体。这是一项由细胞和分子生物学家/生物化学家（David W. Powell 博士）和一名临床肾脏病学家/科学家（Dawn J. Caster 博士）这些研究人员发表了许多研究成果。通过遗传和动物研究，有关 TINIP1/ABIN1 在 LN 中的功能的报告现已准备就绪最近的初步研究结果评估了 TNIP1 多态性在严重程度和影响方面的因果作用人类 LN 的进展和特定细胞和分子事件。这些研究的针对性将提供有影响力的见解，从而实现精确诊断和针对高危非裔美国 LN 患者的治疗方法。

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）

Serum and Urine Interferon Gamma-Induced Protein 10 (IP-10) Levels in Lupus Nephritis.

狼疮性肾炎的血清和尿液干扰素 γ 诱导蛋白 10 (IP-10) 水平。

DOI：
发表时间：
2022-06-03
期刊：
影响因子：
0
作者：
Brady, Makayla P;Chava, Saiteja;Tandon, Shweta;Rane, Madhavi J;Barati, Michelle T;Caster, Dawn J;Powell, David W
通讯作者：
Powell, David W

Living with chronic kidney disease : Perceptions of illness and health-related quality of life

患有慢性肾病：对疾病和健康相关生活质量的看法

DOI：
10.3181/00379727-183-42389
发表时间：
2012-11-12
期刊：
Proceedings of the Society for Experimental Biology and Medicine
影响因子：
0
作者：
A. Pagels
通讯作者：
A. Pagels

A Core Outcome Set for Trials in Glomerular Disease: A Report of the Standardized Outcomes in Nephrology-Glomerular Disease (SONG-GD) Stakeholder Workshops.

肾小球疾病试验的核心结果集：肾脏病学-肾小球疾病 (SONG-GD) 利益相关者研讨会标准化结果报告。

DOI：
发表时间：
2022-01
期刊：
影响因子：
0
作者：
Carter, Simon A;Lightstone, Liz;Cattran, Dan;Tong, Allison;Bagga, Arvind;Barbour, Sean J;Barratt, Jonathan;Boletis, John;Caster, Dawn J;Coppo, Rosanna;Fervenza, Fernando C;Floege, Jürgen;Hladunewich, Michelle A;Hogan, Jonathan J;Kitching, A
通讯作者：
Kitching, A

Management of Lupus Nephritis: New Treatments and Updated Guidelines.

狼疮性肾炎的治疗：新的治疗方法和更新的指南。