SBIR-STTR Award

A key event in the initiation and maintenance of an inflammatory response is the recruitment of immune effector cells to the site of a local immune response. This recruitment and retention is mediated by chemoattractants compounds, of which chemokines are an essential component. The chemokine family consists of about 50 small proteins, which mediate there effects through G-protein coupled chemokine receptors expressed on target cells. The long term objective of this study is to develop a Xenopus oocyte assay system to identify and isolate novel peptidyl agonists / antagonists of the chemokine receptors. In phase I studies, we propose to establish the feasibility of this approach using the CCR3 receptor and eotaxin, a specific agonist of CCR3, to screen for novel CCR3 agonist and antagonist peptides. Having established feasibility in Phase II, we propose to develop this assay for all chemokine receptors (about 18 to date) and to characterize the effectors identified in these screens. PROPOSED COMMERCIAL APPLICATION: Production of a panel of novel effectors for chemokine receptors would provide us with tools for the identification and development of therapeutic compounds based on inhibition of chemokine receptor function. These tools would be of considerable value as general reagents to study the biology of chemokine receptors, and in some case may provide lead effectors for the development of therapeutic approaches.

Thesaurus Terms:
G protein, Xenopus oocyte, chemokine, cytokine receptor, receptor sensitivity, technology /technique development electrophysiology, peptide library, protein sequence, receptor coupling

A key event in the initiation and maintenance of an inflammatory response is the recruitment of immune effector cells to the site of a local immune response. This recruitment and retention is mediated by chemoattractant compounds, of which chemokines are an essential component. The chemokine family consists of ~50 small proteins, which mediate effects through G-protein coupled chemokine receptors expressed on target cells.The long term objective of this study is to isolate and characterize effectors which regulate the chemokine / chemokine receptor interaction. To achieve this our phase I objective was to develop a Xenopus oocyte assay to identify and isolate novel peptidyl agonists / antagonists of the chemokine receptors. In phase I feasibility studies we developed an assay using the CCR3 receptor, and the chemokine eotaxin as a positive control. We also developed a peptide expression system, and initiated library screening.In phase II studies we propose to extend our assay development to all known chemokine receptors, and to characterize the agonist and antagonist effectors isolated in our assay. The results of these studies will be used in the next phase of research, the development of lead compounds

Thesaurus Terms:
G protein, Xenopus oocyte, biological signal transduction, chemokine, cytokine receptor, molecular cloning, receptor expression, receptor sensitivity, technology /technique development electrophysiology, peptide library, protein sequence, protein structure function, receptor coupling