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.
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