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/anti-inflammatory 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.Awardee's statement of the potential commercial applications of the research:The commercial application of the research is the development of pharmacotherapeutics which regulate monocyte functioning via antagonism/agonism of the human monocyte chemoattractant protein-l receptor which will be useful in treatment of a variety of diseases including glomerular nephritis, rheumatoid arthritis, cancer and atherosclerosis. This will be accomplished through development of a novel screening system which utilizes stably transfected cell lines which express high levels of MCP- I receptors.National Institute of General Medical Sciences (NIGMS)
