Variations of Complement in Immunity and Diseases
免疫和疾病中补体的变化
基本信息
- 批准号:6671235
- 负责人:
- 金额:$ 33.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-15 至 2008-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The fourth component of complement (C4) is one of the most polymorphic proteins found in humans and has a wide range of serum levels. Two major isotypes exist, i.e., C4A and C4B, which differ functionally and have many polymorphic variants. Complete or partial C4A deficiency has been reported to be a risk factor for systemic lupus erythematosus (SLE) but this conclusion has been based mainly on phenotypic studies or RFLP analysis for the detection of deleted C4A genes. Furthermore, it is generally presumed that there are a (relatively) constant number of genes among different individuals as proposed for the two-locus model in the MHC with one C4A gene, one C4B gene and null alleles in either locus. We have found that there is actually a frequent, dichotomous gene size variation, polygenic and modular duplications of C4A and C4B together with their flanking genes RP1 or RP2, CYP21A or CYP21B, and TNXA or TNXB in humans. We hypothesize that these variations in gene dosages, protein levels and functions of complement component C4A and C4B confer among different human subjects differential intrinsic strengths of immune responses. We further postulate that under- and over-expression of C4 are risk factors for autoimmune diseases and complement-mediated tissue injuries, respectively. Thus, the long-term goals of this study are to elucidate the sophisticated genetic diversities of C4A and C4B in human populations, and to determine their physiological consequences. The specific aims are: 1) To determine the genetic complexity and protein polymorphisms of human complement components C4A and C4B in Caucasians, Africans, Asians and Hispanics, 2) To investigate the roles of complement C4 gene variation and ligand binding to CR1 in a similar ethnically diverse group of SLE patients, 3) To elucidate the molecular basis of complete complement C4 deficiency in human SLE and kidney disease patients and 4) To develop a non-human primate (macaque) model of complement C4 for studies of polygenic variations, function and disease association. Currently two hypotheses exist for the role of complement in SLE: a) complement is needed to clear apoptotic debris and/or immune complexes (IC), b) complement is needed for the deletion of autoreactive B cells. The information gained from this proposal will help elucidate the role of C4 in autoimmunity, provide a more appropriate animal model for the affect of complement on IC clearance and yield valuable information regarding diagnosis and therapeutic intervention in SLE.
描述(由申请方提供):补体的第四组分(C4)是在人体中发现的最具多态性的蛋白质之一,具有广泛的血清水平。存在两种主要同种型,即,C4 A和C4 B,它们在功能上不同,并且具有许多多态性变体。C4 A完全或部分缺乏已被报道是系统性红斑狼疮(SLE)的一个危险因素,但这一结论主要是基于表型研究或RFLP分析检测缺失的C4 A基因。此外,通常假定在不同个体之间存在(相对)恒定数目的基因,如针对MHC中的两个基因座模型所提出的,其中一个C4 A基因、一个C4 B基因和在任一基因座中的无效等位基因。我们已经发现,在人类中实际上存在C4 A和C4 B及其侧翼基因RP 1或RP 2、CYP 21 A或CYP 21 B以及TNXA或TNXB的频繁的二分基因大小变异、多基因和模块化重复。我们假设,这些基因剂量,蛋白质水平和补体成分C4 A和C4 B的功能的变化赋予不同的人类受试者之间的差异的内在强度的免疫反应。我们进一步假设C4的低表达和过表达分别是自身免疫性疾病和补体介导的组织损伤的危险因素。因此,本研究的长期目标是阐明C4 A和C4 B在人群中的复杂遗传差异,并确定其生理后果。具体目标是:1)确定高加索人、非洲人、亚洲人和西班牙人中人补体成分C4 A和C4 B的遗传复杂性和蛋白质多态性,2)研究补体C4基因变异和配体与CR 1结合在相似种族多样性SLE患者组中的作用,3)阐明人类SLE和肾脏疾病患者完全补体C4缺乏的分子基础; 4)开发非人灵长类动物(猕猴)用于研究多基因变异、功能和疾病关联的补体C4模型。目前存在两种关于补体在SLE中的作用的假设:a)需要补体来清除凋亡碎片和/或免疫复合物(IC),B)需要补体来删除自身反应性B细胞。本研究结果将有助于阐明补体C4在自身免疫中的作用,为研究补体对IC清除的影响提供更合适的动物模型,并为SLE的诊断和治疗提供有价值的信息。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('CHACK Y YU', 18)}}的其他基金
Complement Genetics and Clinical Variability of Systemic Lupus Erythematosus
系统性红斑狼疮的补体遗传学和临床变异
- 批准号:
8327290 - 财政年份:2008
- 资助金额:
$ 33.57万 - 项目类别:
Complement Genetics and Clinical Variability of Systemic Lupus Erythematosus
系统性红斑狼疮的补体遗传学和临床变异
- 批准号:
7906020 - 财政年份:2008
- 资助金额:
$ 33.57万 - 项目类别:
Complement Genetics and Clinical Variability of Systemic Lupus Erythematosus
系统性红斑狼疮的补体遗传学和临床变异
- 批准号:
7467641 - 财政年份:2008
- 资助金额:
$ 33.57万 - 项目类别:
MOLECULAR GENETICS OF THE HUMAN MHC CLASS III REGION
人类 MHC III 类区域的分子遗传学
- 批准号:
7723119 - 财政年份:2008
- 资助金额:
$ 33.57万 - 项目类别:
Complement Genetics and Clinical Variability of Systemic Lupus Erythematosus
系统性红斑狼疮的补体遗传学和临床变异
- 批准号:
7680116 - 财政年份:2008
- 资助金额:
$ 33.57万 - 项目类别:
Complement Genetics and Clinical Variability of Systemic Lupus Erythematosus
系统性红斑狼疮的补体遗传学和临床变异
- 批准号:
8123298 - 财政年份:2008
- 资助金额:
$ 33.57万 - 项目类别:
MOLECULAR GENETICS OF THE HUMAN MHC CLASS III REGION
人类 MHC III 类区域的分子遗传学
- 批准号:
7601294 - 财政年份:2007
- 资助金额:
$ 33.57万 - 项目类别:
Molecular Genetics of the Human MHC Class III Region
人类 MHC III 类区域的分子遗传学
- 批准号:
6980115 - 财政年份:2004
- 资助金额:
$ 33.57万 - 项目类别:
MOLECULAR GENETICS OF THE HUMAN MHC CLASS III REGION
人类 MHC III 类区域的分子遗传学
- 批准号:
7181656 - 财政年份:2004
- 资助金额:
$ 33.57万 - 项目类别:
Variations of Complement in Immunity and Diseases
免疫和疾病中补体的变化
- 批准号:
7257249 - 财政年份:2003
- 资助金额:
$ 33.57万 - 项目类别:
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