SLAM Gene Family Controlled Pathways to SLE

描述(由申请者提供)：该计划项目资助申请汇集了一群在分子和细胞免疫学以及人类和老鼠遗传学领域的专家。我们建议研究SLAM家族基因在系统性红斑狼疮发病机制中的作用，该应用题为：SLAM基因家族控制的SLE通路。由于对患者材料的成功的初步分析和在转基因小鼠中令人兴奋的发现，这项应用试图确定SLAM家族基因变异导致的信号转导途径缺陷是如何导致SLE的发病机制的。我们将把我们最近获得的关于系统性红斑狼疮原因的见解用于以下三个相互关联的项目和两个支持核心： 项目1.确定人类染色体1q23上SLAM基因座上SLE的因果等位基因。 John Rioux和Tim Vyse，蒙特利尔大学，麻省理工学院布罗德研究所和哈佛大学哈默史密斯医院/伦敦帝国理工学院。 项目2.小鼠系统性红斑狼疮中SLAM受体家族通路的遗传解剖。 考克斯·特霍斯特，贝丝以色列女执事医疗中心。 项目3.小鼠系统性红斑狼疮中CD48/CD244受体/配体对的功能分析。 哈佛医学院病理学系阿琳·夏普和伊维特 拉奇曼，华盛顿大学西雅图分校的。 核心A.遗传小鼠核心 王宁海，贝丝以色列女执事医疗中心。 核心B.行政核心，考克斯·特霍斯特，贝丝以色列女执事医疗中心。 总之，该计划中提出的实验应该阐明一个或几个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。这些研究的结果应该建议可应用于SLE患者的治疗策略。 项目1.确定人类染色体1q23上SLAM基因座上SLE的因果等位基因。 John Rioux和Tim Vyse，蒙特利尔大学，麻省理工学院布罗德研究所和哈佛大学哈默史密斯医院/伦敦帝国理工学院。 项目2.小鼠系统性红斑狼疮中SLAM受体家族通路的遗传解剖。 考克斯·特霍斯特，贝丝以色列女执事医疗中心。 项目3.小鼠系统性红斑狼疮中CD48/CD244受体/配体对的功能分析。 哈佛医学院病理学系阿琳·夏普和伊维特 拉奇曼，华盛顿大学西雅图分校的。 核心A.遗传小鼠核心 王宁海，贝丝以色列女执事医疗中心。 核心B.行政核心，考克斯·特霍斯特，贝丝以色列女执事医疗中心。 总之，该计划中提出的实验应该阐明一个或几个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。这些研究的结果应该建议可应用于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 SLAMFamily 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. 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.