This is an integrated program project designed to continue investigations of mesenchymal tissues, their structure, function and alterations in diseases such as an inflammatory joint disease, metabolic bone disease and selected genetic disorders of connective tissue. Approaches to these investigations mainly involve use of techniques of biochemistry and cell and molecular biology. The focus is on connective tissue macromolecules, particularly collagens but also fibronectin and hyaluronic acid, how they interact and how synthesis and degradatin are controlled. Among the aims of this proposal are further understanding of rheumatoid arthritis and the cellular interactions among T lymphocytes, monocyte/macrophages and mesenchyumal cells that govern chronicity and abnormal degradation and synthesis of the extracellular matrix. Mechanisms which govern the excessive production of collagenase and eicosanoids will be defined particularly from the viewpoint of how cytokines function to alter production of the level of the proteins and the genes. Mutant collagens resistant to collagenase will be pepared to further define functions of collagenase. The central role of monocytes as a source of the inflammatory cytokines will be investigated. Mechanisms of T lymphocyte activation are ciritcal to understnading the inflammatory process. The T lymphocytes that grow from rheumatoid synovium are derived from a limited number of clones. Characterization of these clones is a major aim. Bone resorption is carried out by osteoclasts in inflammatory joint disease. How cellular interactions govern differentiation and activation of these cells will be approached using a hematopoitic marrow system and characterizing markers (e.g. calcitonin receptor). The 9 projects are as follows: 1. Collagen Degradation in Inflammation; 2. Collagen Synthesis in Inflammation; 3. Molecular Basis of Hyaluronate Binding Activity; 44. Monocyte Differentiation and Function; 5. T Lymphocyte Function in Inflammation; 6. Genetic Approach to T Cell Activation; 7. Skeletal Cell Differentiation and Responses; 8. Collagen Metabolism in Human Disease; 9. Control of Eicosanoid Metabolism in Inflammation. Interactions of investigation with mutual interests in these projects is at several levels and is critical for conduct of the Program Project as a whole.
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