Our long-term goals are to understand how animal cells regulate their phospholipid makeup and the importance of this in cell function and in human health. Our main focus has been on plasmalogens; a class of phospholipid that constitutes 18 percent of the phospholipid mass in humans and are found in very high levels in heart, muscle and brain (one-third of heart phospholipid is plasmalogen). We have generated mutants from well characterized somatic cell lines, that are defective in plasmalogen biosynthesis. These plasmalogen-deficient cells are hypersensitive to chemical hypoxia (a chemical model for ischemia/ reperfusion), as well as anoxia/reoxygenation. These and other data suggest a role for plasmalogens, as endogenous antioxidants, in the protection of cells and tissues during episodes of ischemia/reperfusion such as heart attack and stroke. In another area of interest, we have attempted to isolate mutants with general defects in, glycerolipid biosynthesis, particularly in the biosynthesis and initial metabolism of phosphatidic acid. We have recently isolated a putative mutant in phosphatidate phosphohydrolase, a key regulatory enzyme in triglyceride synthesis.
Our specific aims for the near future are: 1. To isolate mutants in the first step in diacyl-glycerolipid biosynthesis, sn-glycero-3-phosphate acyltransferase. 2. To isolate the gene(s) involved in the first step in plasmalogen biosynthesis (dihydroxyacetonephosphate acyltransferase), and in overall glycerolipid biosynthesis (phosphatidate phosphohydrolase), using existing mutants that are deficient in these steps. 3. To define the mechanism by which plasmalogens protect cells during chemical hypoxia and anoxia/reperfusion.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050571-06
Application #
6018991
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Haft, Carol Renfrew
Project Start
1993-12-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Boston University
Department
Physiology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Liu, Dailan; Nagan, Narasimhan; Just, Wilhelm W et al. (2005) Role of dihydroxyacetonephosphate acyltransferase in the biosynthesis of plasmalogens and nonether glycerolipids. J Lipid Res 46:727-35
Munn, Natalie J; Arnio, Emily; Liu, Dailan et al. (2003) Deficiency in ethanolamine plasmalogen leads to altered cholesterol transport. J Lipid Res 44:182-92
Zoeller, Raphael A; Grazia, Todd J; LaCamera, Peter et al. (2002) Increasing plasmalogen levels protects human endothelial cells during hypoxia. Am J Physiol Heart Circ Physiol 283:H671-9
Gaposchkin, D P; Zoeller, R A; Broitman, S A (2000) Incorporation of polyunsaturated fatty acids into CT-26, a transplantable murine colonic adenocarcinoma. Lipids 35:181-6
Gaposchkin, D P; Zoeller, R A (1999) Plasmalogen status influences docosahexaenoic acid levels in a macrophage cell line. Insights using ether lipid-deficient variants. J Lipid Res 40:495-503
Zoeller, R A; Lake, A C; Nagan, N et al. (1999) Plasmalogens as endogenous antioxidants: somatic cell mutants reveal the importance of the vinyl ether. Biochem J 338 ( Pt 3):769-76
Nagan, N; Hajra, A K; Larkins, L K et al. (1998) Isolation of a Chinese hamster fibroblast variant defective in dihydroxyacetonephosphate acyltransferase activity and plasmalogen biosynthesis: use of a novel two-step selection protocol. Biochem J 332 ( Pt 1):273-9
James, P F; Lake, A C; Hajra, A K et al. (1997) An animal cell mutant with a deficiency in acyl/alkyl-dihydroxyacetone-phosphate reductase activity. Effects on the biosynthesis of ether-linked and diacyl glycerolipids. J Biol Chem 272:23540-6
Nagan, N; Hajra, A K; Das, A K et al. (1997) A fibroblast cell line defective in alkyl-dihydroxyacetone phosphate synthase: a novel defect in plasmalogen biosynthesis. Proc Natl Acad Sci U S A 94:4475-80
James, P F; Zoeller, R A (1997) Isolation of animal cell mutants defective in long-chain fatty aldehyde dehydrogenase. Sensitivity to fatty aldehydes and Schiff's base modification of phospholipids: implications for Sj-ogren-Larsson syndrome. J Biol Chem 272:23532-9

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