Our long term goal is to determine how signals which are generated by muscarinic receptor-activated inositol phospholipid metabolism are involved in activation of airway smooth muscle function. We also want to learn how production of these signals is controlled or modulated. Our studies currently are performed on porcine trachealis muscle and cultured human ~hypersensitive~ airway muscle. In the present work, we will emphasize investigation of two key enzymes involved in this signal transduction system; inositol phospholipid-specific phospholipase C (PLC), and phosphatidylinositol-4-phosphate 5-kinase (PI(4)P 5-kinase). For PLC, our specific aims are (a) to determine how this enzyme is activated and controlled during muscarinic stimulation; (b) to determine if there is feedback modulation exerted by increases in cytosolic Ca2+ concentration; to determine if phosphatidylinositol transfer protein is involved in delivering substrate to this enzyme.
The specific aim i n studies of cultured human airway smooth muscle which have been treated with TNFa is to determine why these muscles produce more Ins (1,4,5) P3 when activated with bradykinin than do cells which have not been treated with TNFa. In these investigations we use intact airway smooth muscle, subcellular fractions, and cultured human airway smooth muscle cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL037498-11A1
Application #
2396224
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1987-04-01
Project End
2000-06-30
Budget Start
1997-07-10
Budget End
1998-06-30
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Moreland, R S; Coburn, R F; Moreland, S (1995) Decreased PO2 and rabbit aortic smooth muscle mechanics. J Vasc Res 32:313-9
Coburn, R F; Mitchell, H; Dey, R D et al. (1994) Capsaicin-sensitive stretch responses in ferret trachealis muscle. J Physiol 475:293-303