Asthma is a prevalent and chronic disorder characterized by airway hyperresponsiveness and excessive activation of airway smooth muscle. Recently, many advance have been made in understanding the roles of the nervous system and inflammatory mediators in the control of airway tone, and new therapeutic agents have begun to emerge. Despite the development of new specific receptor antagonists, beta adrenergic agents remain the most effective immediate therapy for asthma. As with theophylline and corticosteroids, the mechanism of action of beta agonists on smooth muscle remains incompletely understood. Although beta-agonists, by activating protein kinase A (A-kinase) an alter the ability of contractile agonists to produce the necessary rise in calcium that precedes contraction. Another intracellular kinase, protein kinase C, has a similar effect on agonist- induced calcium release, although it is a more dramatic one. Preliminary data exist to suggest that both A-kinase and protein kinase C may inhibit agonist-induced calcium release by a post-receptor mechanism. We hypothesize that A-kinase and protein kinase C alter intracellular communication in the airway smooth muscle cell by phosphorylating and modifying the function of specific components of the signal transduction pathways. We will investigate the mechanism of these inhibitory effects by studying the effects of both kinases on specific elements of the pathway, including: 1) the formation and degradation of inositolpolyphosphates; 2) the inositoltrisphosphate receptor; 3) the GTP binding protein, which couples receptors to phospholipase C; and 4) phosphatidyl-inositol-specific phospholipase C. These results should clarify the respective mechanisms by which A-kinase and protein kinase C inhibit signal transduction in airway smooth muscle, and may point to important intracellular targets for therapeutic modulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002424-05
Application #
2210037
Study Section
Research Manpower Review Committee (MR)
Project Start
1990-05-01
Project End
1995-04-30
Budget Start
1994-05-20
Budget End
1995-04-30
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104