ABIN1 dysfunction in Lupus Nephritis

狼疮性肾炎中的 ABIN1 功能障碍

• 批准号: 10298483
• 负责人: Dawn Caster
• 金额: $ 59.64万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 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/10298483
• 关键词: Address; African American; Alleles; Animal Experiments; Animals; Autoimmunity; B-Lymphocytes; Binding Proteins; Biological Response Modifiers; Blood; Bone Marrow; CXCL10 gene; Cell Maturation; 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; Outcome; Pathologic; Patients; Peripheral; Physiological; Play; Polyubiquitin; Precision therapeutics; Predisposition; Production; Prognosis; Proteins; Proteinuria; Publishing; 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/antagonist; insight; monocyte; neutrophil; novel diagnostics; personalized diagnostics; podocyte; protein function; racial disparity; risk variant; therapeutic target

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 狼疮性肾炎（LN）是系统性红斑狼疮（SLE）常见的严重并发症， 目前的治疗是有毒的并且经常无效。LN更普遍，更容易引起肾脏疾病。 非裔美国人的失败[1-3]。SLE有很强的遗传成分，但与 遗传易感性对非裔美国人预后的了解很少。以前的研究表明 TNIP 1的变体与SLE和LN易感性相关[4-7]。我们报告说， TNIP 1 rs 4958881多态性与大规模系统性红斑狼疮非裔美国人LN的关系 基因分型研究[8]。我们的初步数据显示rs 4958881变异与严重程度和 非裔美国人的LN进展。TNIP 1编码蛋白ABIN 1，其作为生理调节因子发挥作用。 NF-κB抑制剂，一种重要的免疫调节剂[9，10]。我们以前报道过， 小鼠中ABIN 1的功能导致SLE样自身免疫和肾小球肾炎[8，11，12]。 虽然有证据表明ABIN 1对NF-κ B B的调节在自身免疫和免疫性疾病的发生中起作用， 然而，在知识方面仍然存在一些关键的差距。首先，什么样的分子机制介导ABIN 1- LN的依赖性风险增加，它们对不同的免疫细胞类型有特异性吗？第二，改变 TNIP 1多态性诱导的ABIN 1功能在LN的种族差异中发挥作用？第三，TNIP 1 多态性在非裔美国人中具有不同的病理、分子和细胞效应， 和白色美国人在一起 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 TNIP 1变异rs 4958881在白色和非裔美国人LN中的表达。目标2：确定 TNIP 1变体rs 4958881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 ABIN 1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ABIN 1转基因小鼠。动物实验将结合类似的 目的2中的实验使用从具有TNIP 1 rs 4958881风险的LN患者的血液中分离的相同细胞 变量。 这是一份由细胞和分子生物学家/生物化学家（大卫W.鲍威尔）和一个 临床肾病学家/科学家（Dawn J. Caster博士）。这些研究人员发表了许多 通过遗传学和动物研究，关于TINIP 1/ABIN 1在LN中的功能的报告，现在正准备与 最近的初步研究结果，以评估TNIP 1多态性在严重程度和 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，这将导致精确的诊断， 高风险的非裔美国人LN患者的治疗方法。