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:7257249
- 负责人:
- 金额:$ 28.25万
- 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 2009-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdjuvantAffectAfricanAllelesAnimal ModelAntigen-Antibody ComplexAntigen-Presenting CellsAntigensApoptoticAsiansAustriaAutoimmune DiseasesAutoimmunityBindingBlood CirculationCYP21A2 geneCarbohydratesCaucasiansCaucasoid RaceCell CountChinese PeopleClassCodeComplementComplement 4bComplement ActivationComplement ReceptorComplement component C4Complement component C4aComplexDendritic CellsDepositionDetectionDiagnosisDiploidyDiseaseDisease AssociationEpidemiologic StudiesErythrocytesEthnic groupExhibitsExtracellular Matrix ProteinsFamilyFrequenciesGene DosageGenesGeneticGenetic PolymorphismGenetic VariationGenomeGoalsHalf-LifeHispanicsHumanHydrolysisImmune responseImmunityImmunoglobulin Class SwitchingImmunoglobulin GImmunoglobulin MIncidenceIndividualInfectionInjuryInvestigationKidney DiseasesLeadLectinLengthLigand BindingLigandsLupusLupus ErythematosusMacacaMacaca mulattaMajor Histocompatibility ComplexMannose Binding LectinMediatingMexicanModelingMolecularMolecular GeneticsMonkeysMusNuclear ProteinNuclear ProteinsNucleic Acid Regulatory SequencesNumbersPathway interactionsPatientsPatternPeptidesPhysiologicalPlasmaPlasma ProteinsPlayPopulationPredispositionPrimatesProcessProteinsRaceRangeRelative (related person)ReportingResearchRestriction fragment length polymorphismRisk FactorsRoleSerineSerumSerum ProteinsSeveritiesSteroid 21-MonooxygenaseSymptomsSystemSystemic Lupus ErythematosusTherapeutic InterventionTissuesVariantamino groupanergyautoreactive B cellbasecis acting elementcomplement pathwayexperiencehuman CYP21A2 proteinhuman subjecthydroxyl groupmalemouse modelnonhuman primateprotein expressionprotein kinase Rreaction ratereceptorsize
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(由申请人提供):补体的第四组分(C4)是在人类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C4A和C4B两种主要的同型,它们在功能上存在差异,并且具有许多多态性变异。完全或部分C4A缺乏已被报道为系统性红斑狼疮(SLE)的危险因素,但这一结论主要基于表型研究或检测缺失C4A基因的RFLP分析。此外,一般认为不同个体之间存在(相对)恒定数量的基因,如MHC双位点模型所提出的,即一个C4A基因,一个C4B基因,两个位点均无等位基因。我们发现,在人类中,C4A和C4B及其侧链基因RP1或RP2、CYP21A或CYP21B、TNXA或TNXB实际上存在着频繁的、二分类的基因大小变异、多基因和模块化重复。我们假设,补体组分C4A和C4B的基因剂量、蛋白质水平和功能的这些差异,赋予了不同人类受试者不同的内在免疫反应强度。我们进一步假设C4的过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人类群体中C4A和C4B复杂的遗传多样性,并确定其生理后果。具体目标是:1)确定人类补体成分C4A和C4B在高加索人、非洲人、亚洲人和西班牙人中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CR1结合在种族相似的SLE患者群体中的作用。3)阐明人类SLE和肾病患者完全补体C4缺乏的分子基础;4)建立补体C4的非人类灵长类动物(猕猴)模型,用于研究补体C4的多基因变异、功能和疾病相关性。目前关于补体在SLE中的作用存在两种假设:a)补体需要清除凋亡碎片和/或免疫复合物(IC), b)补体需要清除自身反应性b细胞。本研究获得的信息将有助于阐明C4在自身免疫中的作用,为补体对IC清除的影响提供更合适的动物模型,并为SLE的诊断和治疗干预提供有价值的信息。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations.
- DOI:10.1002/art.39589
- 发表时间:2016-06
- 期刊:
- 影响因子:13.3
- 作者:Chen, Ji Yih;Wu, Yee Ling;Mok, Mo Yin;Wu, Yeong-Jian Jan;Lintner, Katherine E.;Wang, Chin-Man;Chung, Erwin K.;Yang, Yan;Zhou, Bi;Wang, Huanyu;Yu, Denise J. H. C.;Alhomosh, Alaaedin;Jones, Karla;Spencer, Charles H.;Nagaraja, Haikady N.;Lau, Yu Lung;Lau, Chak-Sing;Yu, C. Yung
- 通讯作者:Yu, C. Yung
Cloning and functional analysis of the swine eNOS promoter.
猪 eNOS 启动子的克隆和功能分析。
- DOI:10.1080/10425170701400183
- 发表时间:2008
- 期刊:
- 影响因子:0
- 作者:Shontz,KimberlyM;Zhou,Bi;Yu,CYung;Su,BaogenY
- 通讯作者:Su,BaogenY
Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus.
- DOI:10.1038/gene.2009.10
- 发表时间:2009-07
- 期刊:
- 影响因子:5
- 作者:Wu, Y. L.;Hauptmann, G.;Viguier, M.;Yu, C. Y.
- 通讯作者:Yu, C. Y.
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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:
$ 28.25万 - 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:
$ 28.25万 - 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:
$ 28.25万 - 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:
$ 28.25万 - 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:
$ 28.25万 - 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:
$ 28.25万 - 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:
$ 28.25万 - 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:
$ 28.25万 - 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:
$ 28.25万 - 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:
6671235 - 财政年份:2003
- 资助金额:
$ 28.25万 - 项目类别:
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