Functional Analysis of Complement Receptor 2 as a Lupus Susceptibility Gene

补体受体2作为狼疮易感基因的功能分析

• 批准号: 7263174
• 负责人: SUSAN A. BOACKLE
• 金额: $ 42.6万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263174
• 关键词: 1q32; 5' Untranslated Regions; Address; Affect; African American; Alleles; Alternative Splicing; Antigen Presentation; Antigen-Antibody Complex; Antigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacterial Artificial Chromosomes; Binding; Candidate Disease Gene; Caucasians; Caucasoid Race; Cell physiology; Chinese People; Chromosomes; Code; Cohort Studies; Complement 3d Receptors; Complement Activation; Complement Receptor; Data; Dendritic Cells; Development; Disease; Ethnic group; Evaluation; Exons; Follicular Dendritic Cells; Functional disorder; Genes; Genetic; Genetic Transcription; Haplotypes; Hispanics; Human; Immune response; In Vitro; Individual; Ligand Binding; Link; Linkage Disequilibrium; Lupus; Mature B-Lymphocyte; Membrane Glycoproteins; Minor; Modeling; Mus; Parents; Pathogenesis; Patients; Phenotype; Play; Population; Positioning Attribute; Predisposition; Process; Protein Isoforms; Proteins; RNA Splicing; Research Personnel; Role; Self Tolerance; Single Nucleotide Polymorphism; Susceptibility Gene; System; Systemic Lupus Erythematosus; Systemic Therapy; Testing; To autoantigen; Transgenic Mice; Untranslated Regions; autoreactive B cell; base; cohort; design; gene function; human disease; in vivo; insight; mouse model; novel; programs; transcription factor; vector

DESCRIPTION (provided by applicant): Complement receptor 2 (CR2/CD21) is the strongest candidate gene for lupus susceptibility in the Sle 1c lupus susceptibility interval of the NZM2410 mouse model of lupus, based on structural and functional alterations in its protein products. In humans, CR2 is located in a syntenic genetic interval that is also linked and associated with lupus susceptibility. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of the human CR2 gene reduces gene transcription and alters transcription factor binding. A three SNP haplotype consisting of this SNP plus two other CR2 SNPs is associated with lupus susceptibility in Caucasian and Chinese cohorts containing SLE patients and their parents. The project outlined in this proposal will address the hypothesis that CR2 is a lupus susceptibility gene in humans. The specific aims are to identify the CR2 haplotype blocks that are associated with lupus in different ethnic groups; to fully characterize the effects of the 5'UTR SNP on gene transcription; to determine whether additional SNPs in the CR2 gene alter CR2 function; and to demonstrate the effect of individual SNPs and SNP haplotypes on lupus pathogenesis. First, SNP analyses will be performed in cohorts of African-Americans, Caucasians, Chinese, and Hispanics to define haplotype blocks and their linkage and association with lupus in these four ethnic groups. In concurrent studies, the SNPs in the coding and regulatory domains of the CR2 gene will be examined for functional effects. In the case of the SNP in the 5'UTR, for which a functional effect has already been identified, elaborate studies will be performed to characterize how it alters gene function. For the other SNPs in regulatory and coding domains, a more general evaluation to determine functional significance will be performed before delving more deeply into the mechanisms by which these SNPs may alter gene function. In addition, bacterial artificial chromosome (BAG) transgenic mice expressing individual CR2 SNPs as well as CR2 SNP haplotypes on a murine CR2-deficient background will be generated in order to determine whether specific alleles protect from or promote disease development. These studies will advance our understanding of the role of CR2 as a human lupus susceptibility gene and provide insight into the mechanisms by which it contributes to disease development, leading potentially to CR2-targeted therapies for SLE.

描述（由申请人提供）：根据其蛋白质产物的结构和功能改变，补体受体2（CR2/CD21）是NZM2410狼疮小鼠模型的Sle 1c狼疮易感区间中狼疮易感性最强的候选基因。在人类中，CR2 位于同线性遗传区间，该区间也与狼疮易感性相关。人类 CR2 基因 5' 非翻译区 (UTR) 中的单核苷酸多态性 (SNP) 会减少基因转录并改变转录因子结合。由该 SNP 加上另外两个 CR2 SNP 组成的三个 SNP 单倍型与包含 SLE 患者及其父母的白种人和中国人队列中的狼疮易感性相关。该提案中概述的项目将解决 CR2 是人类狼疮易感基因的假设。具体目标是确定与不同种族狼疮相关的 CR2 单倍型块；全面表征 5'UTR SNP 对基因转录的影响；确定 CR2 基因中的其他 SNP 是否会改变 CR2 功能；并证明单个 SNP 和 SNP 单倍型对狼疮发病机制的影响。首先，将在非裔美国人、白种人、中国人和西班牙裔人群中进行 SNP 分析，以确定这四个种族中的单倍型块及其与狼疮的联系和关联。在同时进行的研究中，将检查 CR2 基因编码和调控域中的 SNP 的功能效应。对于 5'UTR 中的 SNP，其功能效应已被确定，将进行详细研究来表征它如何改变基因功能。对于调控和编码域中的其他 SNP，在更深入地研究这些 SNP 可能改变基因功能的机制之前，将进行更一般的评估以确定功能意义。此外，将产生表达单个 CR2 SNP 以及在小鼠 CR2 缺陷背景上表达 CR2 SNP 单倍型的细菌人工染色体 (BAG) 转基因小鼠，以确定特定等位基因是否能预防或促进疾病的发展。这些研究将加深我们对 CR2 作为人类狼疮易感基因的作用的理解，并深入了解它促进疾病发展的机制，从而有可能导致针对 SLE 的 CR2 靶向疗法。