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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：补体受体2（CR2/CD21）是基于其蛋白质产物的结构和功能变化的NZM2410小鼠模型的SLE 1C狼疮易感性间隔中狼疮易感性的最强候选基因。在人类中，CR2位于同步的遗传间隔中，该间隔也与狼疮易感性相关联。人CR2基因的5'未翻译区（UTR）中的单核苷酸多态性（SNP）减少了基因转录并改变转录因子的结合。由该SNP加上其他两个CR2 SNP组成的三个SNP单倍型与狼疮易感性有关，这些狼疮的易感性在包含SLE患者及其父母的白种人和中国同类中。该提案中概述的项目将解决以下假设：CR2是人类中的狼疮易感基因。具体的目的是确定与不同种族中与狼疮相关的CR2单倍型块；充分表征5'UTR SNP对基因转录的影响；确定CR2基因中的其他SNP是否改变CR2功能；并证明单个SNP和SNP单倍型对狼疮发病机理的影响。首先，SNP分析将在非裔美国人，高加索人，中国人和西班牙裔人群中进行，以定义单倍型障碍，以及他们在这四个族裔中与狼疮的联系以及与狼疮的联系。在并发研究中，将检查CR2基因编码和调节域中的SNP是否有功能效应。对于已经鉴定出功能效应的5'UTR中的SNP，将进行精心设计的研究以表征其如何改变基因功能。对于调节和编码域中的其他SNP，在对这些SNP可能会改变基因功能的机制进行更深入研究之前，将进行更一般的评估以确定功能重要性。此外，将产生表达单个CR2 SNP的细菌人造染色体（BAG）转基因小鼠以及在鼠CR2缺乏的背景上的CR2 SNP单倍型，以确定是否可以保护特定的等位基因免受疾病的影响或促进疾病的发育。这些研究将促进我们对CR2作为人类狼疮易感基因的作用的理解，并洞悉其有助于疾病发展的机制，并可能导致SLE的CR2靶向疗法。