A group of chemotactic cytokines belonging to the """"""""chemokine"""""""" family have recently been identified and molecularly cloned. These include the archetypal alpha and beta subfamily members interleukin-8, a neutrophil selective chemoattractant and the monocyte chemoattractant protein-1 (MCP-1). Chemotactic movement and activation of monocytes, a requisite early process in host defense, is likely regulated predominantly through ligand occupancy of MCP-1 chemokine receptors. Our long term goal is to develop pharmacotherapeutics which intervene in the interaction of MCP1 with its receptor with 2 basic objectives: 1) Immunosuppressive/antiinflammatory modulation of monocyte/macrophage function by blocking chemotactic responses through antagonism of the MCP- 1 receptor. Glomerular nephritis, rheumatoid arthritis, pulmonary diseases and atherosclerosis are primary disease targets, and 2) Proinflammatory modulation of monocyte/macrophage function through development of peptide-based MCP-1 receptor agonists with cancer as a disease target.
The specific aims of this proposal are to 1) molecularly clone the cDNA encoding the MCP-1 receptor and 2) create cell lines which stably and functionally express high levels of MCP-1 receptors. These cell lines will be used to develop an MCP-1 receptor antagonist/agonist screening system to identify candidate pharmacotherapeutic molecules from natural and synthetic compound libraries.
