Abstract

Platelet activating factor (PAF), a phospholipid, has an assigned structure of 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC). It affects the function of several cells and tissues. The most pronounced effect of this compound is on platelets, a blood cell with important role in cardiovascular processes. AGEPC stimulates platelets and also causes rapid turnover of polyphosphoinositides (PPI). The theme is to elucidate the 'mechanism"""""""" and """"""""importance' of AGEPC stimulated PPI turnover in platelets. Based on new experimental findings it is our hypothesis that phosphoinositide phosphodiesterase (phospholipase C) plays a key role in AGEPC stimulated activation of platelets. The following experimental strategies will form the basis of this project [I] To establish characteristics of the key enzyme (phospholipase C) involved in PPI turnover; its regulation by selected agents. [II] Relationship between PPI turnover and AGEPC receptor; Is AGEPC receptor a PPI phosphodiesterase? [III] Study of possible link between PPI turnover and platelet refractoriness (desensitization) to AGEPC. [IV] Study of AGEPC stimulated PPI turnover in platelets with in situ manipulated levels of PPI; or in platelets from pathophysiological states. AGEPC is emerging as a potent mediator (autacoid). PPI turnover is drawing support for being a cell signalling event. How this signal-mechanism is involved in biochemical mode of action of this new mediator (AGEPC) is therefore an important issue. This will be explored using platelets as a model cell.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK035170-01A1
Application #
3233427
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1986-01-01
Project End
1988-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
University of Missouri-Columbia
Department
Type
Schools of Medicine
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211

  Publications

Shukla, S D (1996) Tyrosine kinase activation by PAF leads to downstream gene expression. Adv Exp Med Biol 416:153-5
James-Kracke, M R; Sexe, R B; Shukla, S D (1994) Picomolar platelet-activating factor mobilizes Ca to change platelet shape without activating phospholipase C or protein kinase C;simultaneous fluorometric measurement of intracellular free Ca concentration and aggregation. J Pharmacol Exp Ther 271:824-31
Dhar, A; Shukla, S D (1994) Electrotransjection of pp60v-src monoclonal antibody inhibits activation of phospholipase C in platelets. A new mechanism for platelet-activating factor responses. J Biol Chem 269:9123-7
Zhu, C Y; Shukla, S D (1993) Increased tyrosine kinase activity in pp60c-src immunoprecipitate from platelet activating factor stimulated human platelets: in vitro phosphorylation of a synthetic peptide. Life Sci 53:175-83
Dhar, A; Shukla, S D (1993) Tyrosine kinases in platelet signalling. Br J Haematol 84:1-7
Thurston Jr, A W; Rhee, S G; Shukla, S D (1993) Role of guanine nucleotide-binding protein and tyrosine kinase in platelet-activating factor activation of phospholipase C in A431 cells: proposal for dual mechanisms. J Pharmacol Exp Ther 266:1106-12
Shukla, S D; Paul, A; Klachko, D M (1992) Hypersensitivity of diabetic human platelets to platelet activating factor. Thromb Res 66:239-46
Shukla, S D (1992) Platelet-activating factor receptor and signal transduction mechanisms. FASEB J 6:2296-301
Shukla, S D (1991) Inositol phospholipid turnover in PAF transmembrane signalling. Lipids 26:1028-33
Shukla, S D; Halenda, S P (1991) Phospholipase D in cell signalling and its relationship to phospholipase C. Life Sci 48:851-66

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