This grant is requested to support an ongoing program in basic research aimed at understanding the structural basis and molecular mechanisms underlying the function and regulation of receptors for vasoactive peptides. For this purpose, the P.I. will use the kinin receptor system as a model. Kinins, pro-inflammatory peptides released extracellularly following injury, act through two distinct receptors, B1 and B2, which both belong to the seven transmembrane-domain, G-protein-coupled receptor (GPCR) superfamily. The B2 receptor mediates the actions of bradykinin (BK), whereas the B1 receptor mediates the actions of the carboxypeptidase product des-Arg9BK. The physiological responses to kinins include vasodilatation, smooth muscle spasm, edema, hyperalgesia, pain, modulation of hormone and cytokine release, increased epithelial transport, and cell proliferation. Based on these properties, kinins have been implicated in a number of pathophysiological processes involving injury, inflammation, and healing. In order to understand regulation of peptide action in health and disease, a comprehensive research program with two intimately linked goals focusing on kinin receptors has been developed: 1) to study mechanisms of short-term regulation of B1 and B2 receptors by receptor agonists including desensitization and internalization, and 2) to study mechanisms of long-term regulation of B1 and B2 receptor expression by autocrine mechanisms through receptor agonists and by other factors involved in injury and inflammation. The combined study of B1 and B2 receptors also offers unique opportunities to identify structural requirements in peptide GPCR as the ligands and effectors for these receptors are similar while the receptors themselves show relatively little sequence homology. The goals of the research program will be achieved using established techniques from several disciplines including molecular biology, protein chemistry, and cellular imaging of fluoroprobes. This research program will increase our understanding of the regulation of kinin action in pathophysiological states such as inflammation, and will in turn, provide significant insights into general mechanisms of action and regulation of vasoactive peptides.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM041659-13S1
Application #
6591775
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Cole, Alison E
Project Start
1988-08-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2003-03-31
Support Year
13
Fiscal Year
2002
Total Cost
$77,568
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229