Phospholipids are a diverse group of molecules that are major constituents of animal cell membranes. Although there is a great deal of data concerning the phospholipid makeup of membranes, little is known about the factors which regulate the proportions of lipid species found in a particular biological membrane and specific functional roles for most of the individual phospholipid species have not been identified. The long-term goals of the project are to define the mechanisms involved in regulating the lipid composition of animal cell membranes, to identify functions for individual phospholipid species in cellular processes, and to determine the role of altered lipid metabolism in the disease state. Methods for the selection and isolation of somatic cell mutants, defective in lipid biosynthesis and metabolism will be developed and used. These mutant cell lines will be used as tools to answer questions concerning lipid function and the regulation of lipid biosynthesis and metabolism. These mutants will be also be used to isolate genes involved in lipid biosynthesis.
Specific aims for the next four years will be: 1. Identification of roles for ether-linked lipids in cellular processes using previously isolated somatic cell mutants which are defective in the biosynthesis of the lipids. 2. Isolation of additional mutants in either lipid biosynthesis which bear unique lesions in the pathway. 3. Isolation of mutants defective in an early step in glycerolipid biosynthesis, the microsomal glycerol-3-phosphate acyltransferase. 4. Utilization of existing mutants (isolated in the PI's laboratory) to isolate the genes responsible for fatty aldehyde dehydrogenase and peroxisomal dihydroxyacetonephosphate acyltransferase activities. The former activity is defective in human patients with genetic neuromuscular disorder, Sjogren-Larsson syndrome. These studies should help in understanding the role that ether lipid (a major component of animal cell membranes) play in cellular function. The isolation of the responsible for fatty aldehyde dehydrogenase activity will aid in the evaluation of Sjogren-Larsson patients, make the development of transgenic mouse models for this disease possible, and help to understand the role that the defect in long-chain fatty alcohol metabolism plays in the etiology of this disease.
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