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.