Functional Evaluation of ITGAM SNPs

描述（由申请人提供）：最近发现，在ITGAM基因的DNA序列中有一个小的可遗传基因变化（称为单核苷酸多态性或SNP）的人更容易患狼疮，但仍然不知道为什么DNA的这种变化会增加患病的风险。众所周知，ITGAM基因编码一种名为Mac-1的蛋白质复合物的一部分，这种复合物在血细胞表面表达，对血细胞的正常功能至关重要。Mac-1在调节对环境刺激的免疫反应中很重要，在炎症/免疫反应中对白细胞的正常粘附和运动也很重要。我们假设ITGAM基因中的SNP或SNP组合促进狼疮的发展，因为它们导致改变血细胞行为和功能的Mac-1蛋白的产生。这些变化是对环境挑战的反应，有助于免疫反应，易导致SLE的发展。我们的团队计划通过研究ITGAM DNA和ITGAM蛋白来验证这一想法，这些细胞来自具有这些变体的个体。我们应该能够建立ITGAM蛋白变异导致狼疮的机制。一旦确定了这一点，我们就可以开发出基于ITGAM变体表达的方法来识别有狼疮风险的人，并进一步探索这些ITGAM变体影响的免疫途径。然后，我们可以考虑专门针对ITGAM本身或针对ITGAM变体影响的途径的药物，以更有效和安全地治疗狼疮。我们计划使用转基因技术在小鼠中表达变型ITGAM蛋白，并在已建立的SLE小鼠模型中测试其功能相关性。我们相信，拟议的研究将利用最近的遗传学发现，阐明导致SLE发病的致病遗传变异的生物学机制。

DESCRIPTION (provided by applicant): Recently it was found that people with a small heritable genetic change (known as a single nucleotide polymorphism or SNP) in the DNA sequence of a gene called ITGAM are more likely to have lupus, but it's still not known why this change in DNA increases the risk of disease. It is known that the ITGAM gene encodes part of a protein complex called Mac-1, which is expressed on the surface of blood cells and is essential for their proper function. Mac-1 is important in regulating immune responses to environmental stimuli and is important in the proper adhesion and movement of white blood cells in an inflammatory/immune response. We hypothesize that this SNP, or combinations of SNPs, in the ITGAM gene promote lupus development because they lead to the production of altered Mac-1 proteins which changes blood cell behavior and function. These changes, in response to environmental challenges, contribute to immune responses that predisposes to the development of SLE. Our team plans to test this idea by studying ITGAM DNA and ITGAM protein from blood cells collected from individuals that have these variants. We should be able to establish mechanisms by which ITGAM protein variants contribute to lupus. Once this is established, then we can develop methods to identify people who are at risk of lupus based on expression of ITGAM variant(s), and we further explore the immune pathways that these ITGAM variants affect. We can then consider drugs that specifically target either ITGAM itself or target the pathways that ITGAM variants have an impact on to treat lupus more effectively and safely. We plan to express the variant ITGAM proteins in mice using transgenic technology and test their functional relevance in established murine models of SLE. We believe that the proposed studies will capitalize on the recent genetic findings by elucidating biological mechanisms of causative genetic variants that contribute to SLE pathogenesis. PUBLIC HEALTH RELEVANCE: This project will elucidate mechanisms of recent GWAS and candidate gene based genetic evidence of a role for the ITGAM gene product in the pathogenesis of SLE. SLE is a disease that has both an environmental and genetic basis. Elucidation of the mechanism(s) of action of the genetic variants in SLE will guide future studies in the pathogenesis of and ultimately treatment of this and other inflammatory conditions.