Inflammation, defined by Cotran as the """"""""reactions of vascularized living tissues to local injury"""""""", has many dimensions. The Principal Investigator has worked on the pharmacology of certain peptides that suppress the increased vascular permeability that occurs in tissues during the earliest phase of injury (see E.T. Wei and H.A. Thomas. Anti-Inflammatory Peptide Agonists. Annual Rev. Pharmacol. Toxicol. 33:91-108,1993). This characteristic of inflammation, manifested as swelling. edema, and migration of blood contents into the tissue matrix after injury. is an important determinant for tissue survival and function. Recent studies from the PI's laboratory indicate that there are at least four peptide groups that have the potential to act as """"""""anti-inflammatory peptide agonists"""""""" in the vascular tree. These peptides are members of the corticotropin-releasing factor superfamily, neurotensin family, dynorphin A family and a new class of peptides which was called mystixins. Members of these peptide groups act as suppressers of inflammation after local tissue injury. The goal of the proposed research is to find ideal prototypes of des- tyrosine dynorphin A family peptides that will reduce fluid loss from the vascular compartment after tissue injury. The foreign scientist in this project, Professor G.P. Vlasov of the Institute of Macromolecular compounds (Russian Academy of Sciences), will be the principal co- investigator in this research project. using his past experience in peptide synthesis (design of rigid enkephalin analogs). Prof. Vlasov will design and synthesize various des-Tyr dynorphin A analogs which will be bioassayed in the PI's laboratory. Concurrently, the molecular profile of these analogs will be analyzed by a computer modeling program (Comparative Field Analysis) with the goal of creating more potent and selective prototypes. We hope to a) Define the chemical (structural) characteristics of the peptide molecules that determine their anti-inflammatory actions, and b) Characterize the pharmacology and pathophysiology of these peptides. Laboratory techniques designed to address some of these experimental questions are: a) refinement of in vivo and in vitro methods for quantifying the activity of these compounds on vascular permeability b) synthesis and evaluation of radiolabeled ligands suitable for binding studies and c) use of computerized modeling program suitable for defining the molecular fields of the peptides that determine bioactivity.
