Alkylacetylglycerophosphocholines represent a novel group of bioactive phospholipids capable of producing hypotension, aggregation and degranulation of platelets and neutrophils, inflammatory and allergic responses, anaphylaxis, modulation of Ca2+ uptake, and stimulation of metabolism (phosphatidylinositol turnover, glycogenolysis, and the formation of 20:4 metabolites). A neutral glycerolipid, alkylacetylglycerols, has also been shown to elicit a striking hypotensive response in rats. The work in this renewal is directed toward developing an understanding of the metabolism, regulation, and mechanism of action of these important and unique group of glycerolipid cellular mediators. Experimental systems include platelets (rabbits), alveolar and peritoneal macrophages, neutrophils (human), endothelial cells (rat and human), and rat kidneys and spleens. WKY (normotensive) and SHR (hypertensive) rats are used for in vivo experiments and as organ sources. The proposed projects concern the following issues: (a) Source of arachidonate used by the CoA-independent arachidonoyl transacylase involved in the acylation of lyso-PAF formed during the inactivation of PAF and the purification and characterization of the transacylase responsible; (b) Identification of the acetate acceptor molecule in PAF inactivation; (c) Characterization of acetylhydrolase inhibitors (e.g., acetamide analog of PAF) for cellular investigations; (d) Purification of acetylhydrolase for more complete characterization of properties and the perparation of antibodies for use in regulatory studies; (e) Quantitative aspects of PAF biosynthesis (acetyltransferase vs. choline phosphotransferase, plus the possibilities of methylation and Ca2+-dependent polar head group exchange reactions in the formation of PAF); (f) Purification and characterization of the cholinephosphotransferase responsible for PAF synthesis; (g) The metabolism of alkylacetylglycerols and related """"""""diglyceride type"""""""" lipids; (h) Documentation of the composite ether lipid pathway in a model system (alveolar macrophages) involved in PAF metabolism; (i) Factors that regulate the metabolism and cellular processing of PAF; (j) Subcellular sites and membrane topography of PAF enzymes and products; (k) PAF transport systems (intracellular versus extracellular ); and (1) the metabolism of PAF and regulatory controls in animal models of hypertension (SHR genetic hypertensive rats) and inflammation (cotton pellet induced granulomas).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027109-09
Application #
3338961
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1981-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Oak Ridge Associated Universities
Department
Type
DUNS #
City
Oak Ridge
State
TN
Country
United States
Zip Code
37831
Snyder, F (1997) CDP-choline:alkylacetylglycerol cholinephosphotransferase catalyzes the final step in the de novo synthesis of platelet-activating factor. Biochim Biophys Acta 1348:111-6
Lee, T C; Ou, M C; Shinozaki, K et al. (1996) Biosynthesis of N-acetylsphingosine by platelet-activating factor: sphingosine CoA-independent transacetylase in HL-60 cels. J Biol Chem 271:209-17
Lee, T (1996) Acetylation of sphingosine by PAF-dependent transacetylase. Adv Exp Med Biol 416:113-9
Snyder, F; Fitzgerald, V; Blank, M L (1996) Biosynthesis of platelet-activating factor and enzyme inhibitors. Adv Exp Med Biol 416:5-10
Blank, M L; Smith, Z L; Fitzgerald, V et al. (1995) The CoA-independent transacylase in PAF biosynthesis: tissue distribution and molecular species selectivity. Biochim Biophys Acta 1254:295-301
Snyder, F (1995) Platelet-activating factor and its analogs: metabolic pathways and related intracellular processes. Biochim Biophys Acta 1254:231-49
Snyder, F (1995) Platelet-activating factor: the biosynthetic and catabolic enzymes. Biochem J 305 ( Pt 3):689-705
Lee, T C; Fitzgerald, V; Chatterjee, R et al. (1994) Differentiation induced increase of platelet-activating factor acetylhydrolase in HL-60 cells. J Lipid Mediat Cell Signal 9:267-83
Blank, M L; Smith, Z L; Cress, E A et al. (1994) Molecular species of ethanolamine plasmalogens and transacylase activity in rat tissues are altered by fish oil diets. Biochim Biophys Acta 1214:295-302
Snyder, F (1994) Metabolic processing of PAF. Clin Rev Allergy 12:309-27

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