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:6133656
- 负责人:
- 金额:$ 0.51万
- 依托单位:
- 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 2001-12-31
- 项目状态:已结题
- 来源:
- 关键词:
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定义环境和
导致 SLE 发展和疾病的遗传影响
表现。 因为 SLE 的典型病变是免疫复合物 (IC)
驱动的组织炎症,我们相信这些影响是
部分,IC清除受体缺陷,即红细胞类型
补体受体(E-CR1)。 研究表明,特定缺陷
CR1 发生在 SLE 中。 目前尚不清楚这些缺陷是否是遗传性的
自然的或在疾病期间获得的,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 个 CR1 突变,其中 6 个似乎是分离的
患有 SLE 或正常,以及可能与低 E-CR1 相关的一种
水平。 三种突变似乎影响配体结合。 目标是
该提议是确定这些突变影响 CR1 的程度
功能,并确定这些突变是否有或没有
功能失调的 FcgammaRIIa/FcgammaRIIIa 变体的组合是
与系统性红斑狼疮有关。 这项研究还将试图确定是否获得了
E-CR1 缺陷可防止 SLE 复发或与疾病相关
表现。 因此,该项目的目标是:1)
在一大群研究开始时表征 E-CR1 表型
正常人和 SLE 患者,2) 绘制 CR1 的七个已知突变
正常人和 SLE 患者以确定相对频率,3) Express
并表征 CR1 患者变异,4) 绘制两个已知的 FcgammaR
已知与 SLE 相关的变异,以及 5) 评估 E-CR1 的变化
系统性红斑狼疮 (SLE) 患者在复发和缓解期间。
E-CR1 将在 144 名 SLE 患者和 144 名正常人中进行表征。
CR1、FcgammaRIIa 和 FcgammaRIIa 特定区域的白细胞 cDNA
FcgammaRIIIa会被扩增,已知突变的频率
将被鉴定以确定是否有任何多态性变体或
变异的组合与 SLE 相关。 CR1多态性
将用截短的 CR1 结构表达以确定影响
在特定的功能领域,并且该数据将与
E-CR1 表征以评估完整 CR1 中的突变效应
分子。 最后,E-CR1 将在 50 名 SLE 患者中进行表征
每两个月一次确定 E-CR1 缺陷是否排除,因此
预测 SLE 复发或与特定疾病相关
表现形式。拟议研究的结果应澄清
CR1 的遗传性和后天性缺陷在发病中所起的作用
以及SLE的疾病表现。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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DANIEL J BIRMINGHAM其他文献
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{{ truncateString('DANIEL J BIRMINGHAM', 18)}}的其他基金
Complement in Human Lupus: Deficiencies, Profiles and Complications
人类狼疮的补体:缺陷、概况和并发症
- 批准号:
10188429 - 财政年份:2018
- 资助金额:
$ 0.51万 - 项目类别:
Complement in Human Lupus: Deficiencies, Profiles and Complications
人类狼疮的补体:缺陷、概况和并发症
- 批准号:
10414786 - 财政年份:2018
- 资助金额:
$ 0.51万 - 项目类别:
Genetic variants of CR1& FcgammaR in human SLE nephritis
CR1 的遗传变异
- 批准号:
6570865 - 财政年份:2002
- 资助金额:
$ 0.51万 - 项目类别:
CR1 AND FCYRIIA/IIIA DEFECTS IN THE PATHOGENESIS OF SLE
SLE 发病机制中的 CR1 和 FCYRIIA/IIIA 缺陷
- 批准号:
6341678 - 财政年份:1999
- 资助金额:
$ 0.51万 - 项目类别:
CR1 AND FCYRIIA/IIIA DEFECTS IN THE PATHOGENESIS OF SLE
SLE 发病机制中的 CR1 和 FCYRIIA/IIIA 缺陷
- 批准号:
6137225 - 财政年份:1999
- 资助金额:
$ 0.51万 - 项目类别:
CR1 AND FCYRIIA/IIIA DEFECTS IN THE PATHOGENESIS OF SLE
SLE 发病机制中的 CR1 和 FCYRIIA/IIIA 缺陷
- 批准号:
2746110 - 财政年份:1999
- 资助金额:
$ 0.51万 - 项目类别: