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）：最近的自身免疫全基因组关联研究已经确定了 ITGAM 的编码区多态性 (R77H) 与 SLE 的关联，ITGAM 是编码 CD11b 整联蛋白分子 1 条链的基因。 ITGAM 多态性与不同种族的 SLE 相关，并且还会导致疾病严重程度增加，从而导致 SLE 肾炎发病率增加。我们实验室最近的研究表明，常驻肾巨噬细胞上 CD11b 表达的增加与三种不同 SLE 模型中肾炎的发病相关，并且这种表型会随着临床缓解而逆转。 ITGAM 在人类 SLE 肾活检中也过度表达。由于ITGAM具有多种促炎功能，因此我们推测与SLE相关的ITGAM多态性导致功能获得，从而增加单核细胞的粘附、促炎或促凝血功能。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登记库，其中包含来自正常受试者的 DNA，这些受试者表示愿意重新联系以参与各种研究方案。我们将选择纯合的 R/R 和 H/H 个体进行我们的研究。为了鉴定两个多态性 ITGAM 等位基因的功能差异，我们将确定 R77H ITGAM 多态性是否改变 CD11b 的表达或配体结合特征。我们将确定多态性是否影响表达 CD11b 的单核细胞的吞噬、粘附、迁移及其炎症分子产生的功能。最后，我们将建立带有多态性等位基因的转染细胞系，以更好地研究流动条件下的粘附和下游信号转导事件。这些研究应该帮助我们确定 ITGAM 多态性的功能意义，并可能使我们了解这种多态性如何影响 SLE 的易感性和严重程度。公共健康相关性：本提案的目标是确定与人类 SLE 相关的 ITGAM 基因中 R77H 编码区多态性的功能意义。 ITGAM 编码白细胞和单核细胞上表达的 CD11b 粘附分子的 α 链。该方法将使用ITGAM 两种等位基因形式纯合的外周血正常个体来分析CD11b 的表达以及单核细胞在粘附、迁移和促炎分子表达方面的功能。