Genetic variants of CR1& FcgammaR in human SLE nephritis

CR1 的遗传变异

• 批准号: 6570865
• 负责人: DANIEL J BIRMINGHAM
• 金额: $ 29.59万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6570865
• 关键词: CD antigens; complement receptor; flow cytometry; gene mutation; genetic mapping; genetic polymorphism; genetic screening; genetic susceptibility; human subject; immune complex; kidney; longitudinal human study; nephritis; nucleic acid quantitation /detection; pathologic process; patient oriented research; phenotype; polymerase chain reaction; protein structure function; receptor expression; relapse /recurrence; statistics /biometry; systemic lupus erythematosus; tissue /cell culture; western blottings

The long-term goals of this research are to define the various factors that lead to nephritis in SLE. We postulate that, because SLE nephritis is driven by IC deposition, factors that decrease safe IC clearance. In this proposal, we hypothesize that SLE patients with genetic defects in IC clearance receptors (erythrocyte type one complement receptor (E-CR1), FcgammaRIIa, and FcgammaRIIIa) are prone to develop nephritis. Furthermore, we hypothesize that acquired E-CR1 defects that are known to occur in SLE predict and/or influence SLE nephritis relapse. To test these hypotheses, the aims of this proposal are to 1) Characterize E-CR1 phenotypes at study entry in 500 SLE patients, half of whom have renal involvement, and 250 normals, 2) Determine the frequencies of eight CR1 mutations in these study populations which appear to be associated with SLE nephritis and/or are affect CR1 function or presentation, 3) Express and characterize and characterize the CR1 variants in truncated, single-domain CR1 constructs, 4) Map two FcgammaR variants which affect FcgammaR function and which have been implicated as playing a role in SLE nephritis, and 5) Assess serial changes in E-CR1 levels and function in 100 frequently relapsing SLE patients, half of whom have renal involvement, during a 5 year period of relapse and remission. The characterization of the CR1 and FcgammaRIIa/FcgammaRIIIa variants will reveal if specific polymorphisms are associated with SLE nephritis. Exploratory statistical analyses will be done on various combinations of polymorphisms as a first step in identifying if any combinations provide a stronger or unique association with SLE nephritis or SLE in general. For CR1, expression studies in truncated, single- domain CR1 constructs will identify any functional consequence associated with each mutation. Comparing the expression data with E- CR1 characterization collected at study entry will clarify how any difference at a single functional domain is revealed in the intact CR1 molecule containing multiple functional domains. The E-CR1 data will also serve as a baseline for the longitudinal study assessing the serial changes between E-CR1 and SLE relapse, both renal and non-renal. Thus, the longitudinal study will define whether acquired E-CR1 defects predict and/or influence SLE relapse severity or frequency. In summary, these studies should identify the extent that defects in IC clearance proteins contribute to SLE nephritis, SLE in general, and to the frequency and severity of SLE relapse.

本研究的长期目标是确定导致SLE肾炎的各种因素。我们假设，由于SLE肾炎是由IC沉积驱动的，降低IC安全清除的因素。在本研究中，我们假设IC清除受体（红细胞1型补体受体（E-CR1）、Fc γ RIIa和Fc γ RIIIa）基因缺陷的SLE患者易于发生肾炎。此外，我们推测，获得性E-CR1缺陷是已知发生在SLE预测和/或影响SLE肾炎复发。为了验证这些假设，本提案的目的是1）在500名SLE患者（其中一半有肾脏受累）和250名正常人中表征研究入组时的E-CR1表型，2）确定这些研究人群中似乎与SLE肾炎相关和/或影响CR1功能或表现的8种CR1突变的频率，3）在截短的单结构域CR1构建体中表达和表征CR1变体，4）定位影响Fc γ R功能并被认为在SLE肾炎中起作用的两种Fc γ R变体，和5）评估100例频繁复发的SLE患者在复发和缓解的5年期间E-CR1水平和功能的系列变化，其中一半患者有肾脏受累。CR1和Fc γ RIIa/Fc γ RIIIa变体的特征将揭示特定多态性是否与SLE肾炎相关。将对多态性的各种组合进行探索性统计分析，作为确定任何组合是否提供与SLE肾炎或一般SLE的更强或独特关联的第一步。对于CR1，在截短的单结构域CR1构建体中的表达研究将鉴定与每个突变相关的任何功能后果。将表达数据与研究开始时收集的E-CR1表征进行比较，将阐明在含有多个功能结构域的完整CR1分子中如何揭示单个功能结构域的任何差异。E-CR1数据也将作为纵向研究的基线，评估E-CR1和SLE复发（肾性和非肾性）之间的系列变化。因此，纵向研究将确定获得性E-CR1缺陷是否预测和/或影响SLE复发的严重程度或频率。总之，这些研究应该确定IC清除蛋白缺陷在SLE肾炎、SLE总体以及SLE复发的频率和严重程度中的作用程度。