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CR1 AND FCYRIIA/IIIA DEFECTS IN THE PATHOGENESIS OF SLE

SLE 发病机制中的 CR1 和 FCYRIIA/IIIA 缺陷

基本信息

批准号：
6341678
负责人：
DANIEL J BIRMINGHAM
金额：
$ 7.14万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-15 至 2001-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6341678
关键词：
CD antigens CD16 molecule biomarker clinical research complement receptor gene environment interaction gene frequency gene mutation genetic mapping genetic polymorphism genetic susceptibility human subject immune complex receptor binding relapse /recurrence systemic lupus erythematosus

项目摘要

The long-term goal of this research is to define the environmental and genetic influences that lead to the development of SLE and to disease manifestation. Because the classic lesion in SLE is immune complex (IC) driven tissue inflammation, we believe that these influences are, in part, defects in IC clearance receptors, namely erythrocyte type on complement receptor (E-CR1). Studies indicate that specific defects in CR1 occur in SLE. It is not known if these defects are genetic in nature or are acquired during disease, or whether these defects can affect or predict disease severity. In support of genetic defects, we have recently identified 7 CR1 mutations, 6 which appear to segregate with SLE or normals, and one which may be associated with low E-CR1 levels. Three mutations appear to affect ligand binding. The goal of this proposal is determine the extent that these mutations affect CR1 function, and to establish if these mutations, with or without combinations of dysfunctional FcgammaRIIa/FcgammaRIIIa variants, are associated with SLE. This study will also seek to determine if acquired E-CR1 defects preclude SLE relapse or are associated with disease manifestation. Accordingly, the aims of this project are to: 1) Characterize E-CR1 phenotypes at study entry in a large cohort of normals and SLE patients, 2) Map the seven known mutation for CR1 in the normals and SLE patients to determine relative frequencies, 3) Express and characterize the CR1 patients variants, 4) Map two known FcgammaR variants known to be associated with SLE, and 5) Assess changes in E-CR1 in SLE patients during periods of relapse and remission. E-CR1 will be characterized in 144 SLE patients and 144 normals. Leukocyte cDNA for specific regions of CR1, FcgammaRIIa, and FcgammaRIIIa will be amplified, and the frequency of known mutations will be identified to determine if any polymorphic variant or combination of variants are associated with SLE. The CR1 polymorphisms will be expressed in truncated CR1 constructs to determine the affects on specific functional domains, and this data will be compared to the E-CR1 characterization to assess mutation effects in the intact CR1 molecule. Finally, E-CR1 will be characterized in 50 SLE patients at bi-monthly intervals to determine if E-CR1 defects preclude, and thus predict, SLE relapse, or are associated with specific disease manifestations. The results of the proposed studies should clarify the roles that both genetic and acquired defects in CR1 play in the onset and disease manifestation of SLE.

这项研究的长期目标是确定环境和导致SLE发展和疾病的遗传影响表现。由于SLE的经典病变是免疫复合物（IC）驱动的组织炎症，我们认为，这些影响，在部分，IC清除受体的缺陷，即红细胞类型补体受体（E-CR 1）。研究表明， CR 1发生于SLE。目前尚不清楚这些缺陷是否是遗传性的，自然或在疾病期间获得，或者这些缺陷是否可以影响或预测疾病的严重程度。为了支持遗传缺陷，我们最近发现了7种CR 1突变，其中6种似乎与 SLE或正常人，以及可能与低E-CR 1相关的一种程度. 三种突变似乎影响配体结合。的目标这项建议是确定这些突变影响CR 1的程度，功能，并确定这些突变，有或没有功能障碍性Fc γ RIIa/Fc γ RIIIa变体的组合，与SLE相关。这项研究还将试图确定是否获得 E-CR 1缺陷阻止SLE复发或与疾病相关表现。因此，本项目的目标是：1）在一个大型队列中描述研究入组时的E-CR 1表型，正常人和SLE患者，2）绘制CR 1的七个已知突变，正常人和SLE患者，以确定相对频率，3）表达并表征CR 1患者的变体，4）绘制两个已知的Fc γ R 已知与SLE相关的变异，和5）评估E-CR 1的变化在SLE患者的复发和缓解期。将在144名SLE患者和144名正常人中表征E-CR 1。 CR 1、Fc γ RIIa和 Fc γ RIIIa将被扩增，并且已知突变的频率以确定是否存在任何多态性变体或变异的组合与SLE相关。 CR 1多态性将在截短的CR 1构建体中表达，以确定在特定的功能域上，这些数据将与 E-CR 1表征，以评估完整CR 1中的突变效应分子。最后，E-CR 1将在50名SLE患者中进行表征，每两个月一次，以确定是否排除E-CR 1缺陷，预测、SLE复发或与特定疾病相关表现。拟议研究的结果应澄清 CR 1的遗传和获得性缺陷在发病中的作用和SLE的疾病表现。