SLAM Gene Family Controlled Pathways to SLE

描述（由申请人提供）：该计划项目拨款申请汇集了一组研究人员，他们是分子和细胞免疫学以及人类和小鼠遗传学领域的专家。我们提议在一项申请中研究 SLAM 家族基因在系统性红斑狼疮发病机制中的作用，该申请的标题为：“Slam 基因家族控制的 SLE 途径”。由于对患者材料的成功初步分析和基因改造小鼠中令人兴奋的发现，本申请旨在确定由 SLAM-Family 基因座变异基因引起的信号转导途径缺陷如何影响 SLE 的发病机制。我们将利用最近获得的对 SLE 成因的见解来开展以下三个相互关联的项目和两个支持核心： 项目 1. 识别人类染色体 1q23 上 SLAM 基因座中 SLE 的致病等位基因。 John Rioux 和 Tim Vyse，蒙特利尔大学、麻省理工学院和哈佛大学布罗德研究所以及伦敦帝国学院哈默史密斯医院。 项目 2. 小鼠 SLE 中 SLAM 受体家族通路的基因剖析。 考克斯·特霍斯特，贝斯以色列女执事医疗中心。 项目 3. 小鼠 SLE 中 CD48/CD244 受体/配体对的功能分析。 Arlene Sharpe，哈佛医学院病理学系和 Yvette 拉奇曼，华盛顿大学西雅图分校。 核心 A. 基因小鼠核心 王宁海，贝斯以色列女执事医疗中心。 核心 B. 行政核心，考克斯特霍斯特，贝斯以色列女执事医疗中心。 该计划中提出的实验应共同阐明一个或多个 SLAM 家族基因如何控制对染色质和其他细胞内成分的耐受性，从而控制对人类和小鼠狼疮的易感性。这些研究的结果应提出可应用于 SLE 患者的治疗策略。

DESCRIPTION (provided by applicant): This Program Project Grant Application brings together a group of investigators who are experts in the areas of molecular and cellular immunology and human and mouse genetics. We propose to study the role of the SLAM-Family genes in the pathogenesis of Systemic Lupus Erythematosus in an application, which, is entitled: "Slam Gene Family controlled pathways to SLE". Because of successful preliminary analyses of patient materials and exciting findings in genetically altered mice, this application seeks to define how defects in signal transduction pathways caused by variant genes of the SLAM-Family locus contribute to the pathogenesis of SLE. We will use our recently acquired insights into the causes of SLE for the following three interlinked projects and two supporting Cores: Project 1. Identifying the causal alleles for SLE in the SLAM locus on human chromosome 1q23. John Rioux and Tim Vyse, University of Montreal, Broad Institute at MIT and Harvard and Hammersmith Hospital / Imperial College London. Project 2. Genetic dissection of the SLAM-receptor-family pathways in murine SLE. Cox Terhorst, Beth Israel Deaconess Medical Center. Project 3. Functional analyses of the CD48/CD244 receptor/ligand pair in murine SLE. Arlene Sharpe, Department of Pathology of the Harvard Medical School and Yvette Latchman, University of Washington at Seattle. Core A. Genetic Mouse Core Ninghai Wang, Beth Israel Deaconess Medical Center. Core B. Administrative Core, Cox Terhorst, Beth Israel Deaconess Medical Center. Together the experiments that are proposed in the Program should clarify how one or several of the SLAM Family genes control tolerance to chromatin and other intracellular components and consequently susceptibility to human and murine lupus. The results of these studies should suggest therapeutic strategies that can be applied to SLE patients.