The objective of this research is to characterize the biochemical and structural features of the components of kinin-forming systems in rodent plasma and both normal and neoplastic tissue. The components to be studied include both alkaline (kallikrein) and acid kinin-forming proteases, kininogen substrates, vasoactive peptides formed by the interaction of respective proteases and kininiogen substrates and kinin-destroying (kininase) enzymes. This long-term objective will be achieved by studying the detailed physical-chemical and structural aspects of each molecular species as well as the protein-protein interactions. The study of the role of the carbohydrates in the function of such glycoprotein components as kallikrein and kininogen will be a central specific aim of this research. Carbohydrate moieties of glycoproteins have been shown to be functionally involved in protein aggregation or oligomerization similar to that observed with rat plasma kininogen. These moieties from glycoprotein components derived from different tissue sources including neoplastic and blood will be compared and their structure-function (esterolytic and kinin-forming) relationships studied. In view of the involvement of the kinin-forming systems in a wide variety of physiological and pathologic conditions, clarification of molecular factors influencing kinin formation may contribute to our understanding and possibly control of the respective process. This research also proposes to study the cellular site of localization and biosynthesis of major components of the kinin-forming system. Immunohistochemical and tissue perfusion with tritiated amino acids technique will be utilized. The component molecular species derived from the perfusion studies will be compared with system components purified from normal and malignant tissue and blood. Knowledge of the site(s) of synthesis of the kinin-forming enzymes and substrates should help us define more precisely the role of the kinin-forming systems in health and disease
