Inflammation is the major mechanism of diseases mediated by blood cells and plasma proteins. Inflammatory responses underlies a variety of human diseases including atherosclerosis, coronary and peripheral arterial disorders exemplified by Kawasaki disease and systemic lupus (SLE), acute and chronic lung diseases (asthma, acute respiratory distress syndrome, interstitial lung disease), and a variety of vascular diseases including vasooclusive crises in sickle cell anemia. The overall goals of the proposed Program are (i) to conduct genome-wide mutagenesis to select novel genes involved in inflammatory response; (ii) to analyze novel genes at the level of blood lineage specific expression and stimulus-response coupling; (iii) to analyze novel genes in animal models and stimulus-response coupling; (iii) to analyze novel genes in animal models of systemic and localized inflammatory response; and (iv) to determine the function of novel genes in development and signaling of phagocytic and mast cells, T lymphocyte subsets, and B lymphocytes. The currently available resources such as the library of the murine embryonal stem (ES) cell clones with disrupted genes (approximately 600) will be expanded using a new generation of vectors. The Program is a tightly knit organization of highly interactive and cohesive projects and cores: Genetic & Proteomic Analysis of Inflammation; Phagocytosis-Based Functional Genomics of Inflammation; T Lymphocyte-Based Functional of Inflammation; B Lymphocyte-Based Functional Genomics; the Microarrays Core to develop a mutant library microarrays and a new pro-inflammatory gene expression microarrays; the Animal Models Core to screen and analyze phenotype of mutant mice; the Bioinformatics Core to develop a new inflammatory gene database; and the Administrative Core will coordinate this Program to generate, analyze, and share new quality data on genetics and proteomics of inflammation to advance new diagnostic and therapeutic approaches to the diseases of cardiovascular, pulmonary, and blood systems mediated by inflammatory response.
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