Therapeutic Development of Human MCP-1 Receptors

A group of chemotactic cytokines belonging to the "chemokine" family have recently beenidentified and molecularly cloned. These include the archetypal alpha and beta subfamily membersinterleukin-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 longterm goal is to develop pharmacotherapeutics which intervene in the interaction of MCP1 with itsreceptor with 2 basic objectives: 1) Immunosuppressive/anti-inflammatory modulation of mono-cyte/macrophage function by blocking chemotactic responses through antagonism of the MCP-1receptor. Glomerular nephritis, rheumatoid arthritis, pulmonary diseases and atherosclerosis are primarydisease targets, and 2) Pro-inflammatory modulation of monocyte/macrophage function throughdevelopment of peptide-based MCP-1 receptor agonists with cancer as a disease target. The specificaims of this proposal are to 1) molecularly clone the cDNA encoding the MCP-1 receptor and 2) createcell lines which stably and functionally express high levels of MCP-1 receptors. These cell lines will beused to develop an MCP-1 receptor antagonist/agonist screening system to identify candidatepharmacotherapeutic molecules from natural and synthetic compound libraries.