GENETIC AND CLINICAL RISK FACTORS FOR HUMAN SLE NEPHRITIS

人类系统性红斑狼疮肾炎的遗传和临床危险因素

• 批准号: 7625430
• 负责人: LEE A. HEBERT
• 金额: $ 0.31万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-23 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625430
• 关键词: Antigen-Antibody Complex; Biopsy; Clinical; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Defect; Disease; Event; Funding; Genetic; Genetic Polymorphism; Genetic screening method; Gonadal Steroid Hormones; Grant; Human; Immunologics; Immunosuppression; Infection; Inflammation; Institution; Kidney; Measures; Mediating; Molecular Genetics; Nephritis; Parents; Patients; Prospective Studies; Proteins; Recurrent disease; Relapse; Research; Research Design; Research Personnel; Resources; Risk Factors; Severities; Severity of illness; Siblings; Source; Stress; Susceptibility Gene; Systemic Lupus Erythematosus; Testing; Therapeutic immunosuppression; Time; Ultraviolet Rays; United States National Institutes of Health; chemokine; concept; follow-up; genetic analysis; tool; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nephritis is a frequent and severe manifestation of human SLE. Long-term immunosuppression is usually necessary. Relapse is common. SLE nephritis is the result of glomerular accumulation of immune complexes (IC). The risk factors for renal involvement, as well as the determinants of relapse and severity, are poorly understood. We postulate that 1) The dominant mechanism for glomerular IC accumulation is genetic and/or acquired defects of IC clearance proteins. Furthermore, the concurrence of 2 or more defective/deficient IC clearance proteins predisposes to severe nephritis. 2) IC mediate renal inflammation by regulating the local expression of chemotactic cytokines (chemokines). 3) Specific, quantifiable clinical events are triggers for SLE nephritis relapse, and influence disease severity. These hypotheses will be tested by 4 interrelated projects. Projects 1 and 2 analyze genetic polymorphisms of key IC clearance proteins (C2, C4, CR1,FcgRIIa, and FcgRIIIa), to determine which are susceptibility genes for human SLE nephritis. Project 3 examines genetic, molecular, and cellular mechanisms that regulate chemokine activity in human SLE nephritis. The genetic testing of Projects 1, 2, and 3 will involve 250 SLE nephritis patients (biopsy proven), 250 SLE patients who have never had nephritis, and 250 matched normals. Parents and siblings of the SLE patients will also be used for transmission disequilibrium testing (TDT). Project 4 is a meticulous, prospective study designed to determine the relationship between SLE relapse and genetic, immunologic, and clinical parameters. One hundred SLE patients with relapsing disease (50 with and 50 without renal manifestations) will be studied longitudinally over 5 years. In collaboration with Projects 1-3, serial quantitative measures of IC clearance proteins, chemokines, and specific clinical factors (stress, sex hormones, infection, UV radiation) will be obtained before, during, and after each of the more than 300 SLE relapses expected during follow-up. These variables will be correlated to disease activity and severity to determine which are "triggers" for SLE relapse, and which are determinants of the renal manifestations of SLE. From this analysis should emerge, for the first time, a clear picture of the risk factors for SLE nephritis and its relapse in humans. Summary: Concepts fundamental to understanding the genetic and clinical risk factors for human SLE nephritis should be revealed, thus providing tools for predicting SLE nephritis relapse and severity, and strategies for its management

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 肾炎是人类 SLE 的常见且严重的表现。 通常需要长期免疫抑制。 复发很常见。 SLE 肾炎是肾小球内免疫复合物 (IC) 积聚的结果。 人们对肾脏受累的危险因素以及复发和严重程度的决定因素知之甚少。 我们假设 1) 肾小球 IC 积累的主要机制是 IC 清除蛋白的遗传和/或后天缺陷。 此外，同时存在两种或多种缺陷/缺陷的IC清除蛋白易患严重肾炎。 2）IC通过调节趋化细胞因子（趋化因子）的局部表达来介导肾脏炎症。 3) 特定的、可量化的临床事件是 SLE 肾炎复发的触发因素，并影响疾病的严重程度。这些假设将通过 4 个相互关联的项目进行检验。 项目1和2分析了关键IC清除蛋白（C2、C4、CR1、FcgRIIa和FcgRIIIa）的遗传多态性，以确定哪些是人类SLE肾炎的易感基因。 项目 3 研究调节人类 SLE 肾炎趋化因子活性的遗传、分子和细胞机制。 项目1、2和3的基因检测将涉及250名SLE肾炎患者（活检证实）、250名从未患过肾炎的SLE患者以及250名匹配的正常人。 SLE 患者的父母和兄弟姐妹也将被用于传递不平衡测试 (TDT)。 项目 4 是一项细致的前瞻性研究，旨在确定 SLE 复发与遗传、免疫和临床参数之间的关系。 将在 5 年内对 100 名患有复发性疾病的 SLE 患者（50 名有肾脏表现和 50 名没有肾脏表现）进行纵向研究。 与项目 1-3 合作，将在随访期间预期的 300 多个 SLE 复发之前、期间和之后获得 IC 清除蛋白、趋化因子和特定临床因素（压力、性激素、感染、紫外线辐射）的系列定量测量。 这些变量将与疾病活动性和严重程度相关，以确定哪些是 SLE 复发的“触发因素”，哪些是 SLE 肾脏表现的决定因素。 从这项分析中，我们将首次清楚地了解 SLE 肾炎的危险因素及其在人类中的复发。 摘要：应该揭示理解人类 SLE 肾炎的遗传和临床危险因素的基本概念，从而提供预测 SLE 肾炎复发和严重程度的工具及其管理策略