Functional significance of an ITGAM polymorphism in SLE

ITGAM 多态性在 SLE 中的功能意义

基本信息

批准号：
8014906
负责人：
Anne Davidson
金额：
$ 14.34万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8014906
关键词：
Adhesions Affect Alleles Amino Acid Substitution Autoimmune Diseases Autoimmunity Biopsy Cell Adhesion Molecules Cell Line Cell surface Characteristics Coagulants Code DNA Disease Enrollment Ethnic group Event Explosion Genes Genetic Polymorphism Genetic Variation Genotype Goals Haplotypes Human ITGAM gene Incidence Individual Inflammatory Integrins Kidney Laboratories Leukocytes Ligand Binding Lupus Measures Modeling Nephritis Phagocytosis Phenotype Phosphorylation Population Predisposition Production Protocols documentation Registries Research Resources Risk Severities Severity of illness Signal Transduction Solvents Systemic Lupus Erythematosus Testing Time Variant base cell motility clinical remission cytokine gain of function genetic association genome wide association study interest mRNA Expression macrophage migration monocyte overexpression particle peripheral blood public health relevance willingness

项目摘要

DESCRIPTION (provided by applicant): Recent genome-wide association studies in autoimmunity have identified the association of a coding region polymorphism (R77H) of ITGAM, a gene that encodes for the 1 chain of the CD11b integrin molecule, with SLE. The ITGAM polymorphism is associated with SLE across ethnic groups and also confers increased disease severity with an increased incidence of SLE nephritis. Recent studies from our laboratory have shown that increased expression of CD11b on resident renal macrophages is associated with nephritis onset in three different SLE models and that this phenotype reverses concomitant with clinical remission. ITGAM is also overexpressed in human SLE renal biopsies. Since ITGAM has multiple pro-inflammatory functions we therefore hypothesize that the ITGAM polymorphism associated with SLE results in a gain of function such that there is increased adhesion, pro-inflammatory or pro-coagulant function of monocytes. To test this hypothesis we will utilize a unique very large normal subject registry containing DNA from normal subjects who express a willingness to be re-contacted to participate in various research protocols. We will select homozygous R/R and H/H individuals for our study. To identify functional differences in the two polymorphic ITGAM alleles we will establish whether the R77H ITGAM polymorphism alters expression or ligand binding characteristics of CD11b. We will determine whether the polymorphism affects the function of monocytes expressing CD11b with respect to their phagocytosis, adhesion, migration and their production of inflammatory molecules. Finally, we will establish transfected cell lines bearing the polymorphic alleles to better study adhesion under flow conditions and downstream signal transduction events. These studies should help us identify the functional significance of the ITGAM polymorphism and may allow us to understand how this polymorphism affects the susceptibility to and severity of SLE. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to determine the functional significance of the R77H coding region polymorphism in the ITGAM gene that is associated with human SLE. ITGAM encodes the alpha chain of the CD11b adhesion molecule expressed on leukocytes and monocytes. The approach will be to use peripheral blood normal individuals homozygous for the two allelic forms of ITGAM to analyze the expression of CD11b and the function of monocytes with respect to adhesion, migration and expression of pro-inflammatory molecules.

描述（由申请人提供）：自身免疫性的最新基因组关联研究已经确定了ITGAM的编码区多态性（R77H）的关联，该基因编码为CD11b整合蛋白分子的1链，与SLE的1链。 ITGAM多态性与跨种族的SLE有关，并且同意增加疾病的严重程度，而SLE肾炎的发生率增加。我们实验室的最新研究表明，在三种不同的SLE模型中，CD11b在居民肾脏巨噬细胞上的表达增加与肾炎发作有关，并且该表型逆转与临床缓解相关。 ITGAM在人类SLE肾脏活检中也过表达。因此，由于ITGAM具有多种促炎功能，因此我们假设与SLE相关的ITGAM多态性会导致功能增长，从而增加了单核细胞的粘附，促炎或促凝功能。为了检验这一假设，我们将利用一个独特的非常大的正常受试者注册表，其中包含来自正常受试者的DNA，他们表示愿意重新接触参加各种研究方案。我们将选择纯合R/R和H/H个人进行研究。为了确定两个多态性ITGAM等位基因中的功能差异，我们将确定R77H ITGAM多态性是改变CD11b的表达还是配体结合特性。我们将确定多态性是否影响表达CD11b的单核细胞相对于其吞噬，粘附，迁移及其产生炎症分子的功能。最后，我们将建立带有多态等位基因的转染细胞系，以更好地研究流动条件和下游信号转导事件的粘附。这些研究应有助于我们确定ITGAM多态性的功能意义，并可能使我们能够了解这种多态性如何影响SLE的易感性和严重性。公共卫生相关性：该提案的目的是确定与人SLE相关的ITGAM基因中R77H编码区多态性的功能意义。 ITGAM编码在白细胞和单核细胞上表达的CD11b粘附分子的α链。该方法将是使用纯合的外周血正常个体对ITGAM的两种等位基因形式进行分析，以分析CD11b的表达以及单核细胞在粘附，迁移和促炎分子的表达方面的功能。