This proposal represents a continuation of the applicant's interest in lipid metabolism in disorders of cornification. There are two major thrusts to this work. First, the applicant will explore the mechanisms of sterol regulation in the skin. Since it has been shown that lipoprotein cholesterol does not regulate epidermal cholesterol synthesis, the candidate will determine whether stratum corneum polar sterols such as cholesterol sulfate or oxygenated sterols are regulators. In addition to sterologenesis, the applicant will also study another product of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, the rate-limiting enzyme of the cholesterol biosynthetic pathway, that is potentially important for energy production (ubiquinones) in the epidermis. To resolve these points the applicant first will utilize normal cultured human fibroblasts, attempting to validate cell culture results in organ culture and the whole animal. Elucidation of epidermal sterol metabolism is likely to provide important insights not only into sterologenesis, but also into more general effects of HMGCoA products on cell function. The second major thrust is aimed at a further elucidation of the lipid abnormalities in inherited recessive disorders of cornification. Since intercellular lipids appear to be one factor that controls desquamation, discovery of the basic defect in these diseases will provide new insights both into the role of certain lipids in normal epidermal function, and more rational approaches to therapy of these sometimes devastating diseases. In addition to the well-appreciated importance of sterols for cornification, best exemplified by fork of the applicant and others on recessive x-linked ichthyosis, the applicant is studying two autosomal recessive diseases: a) non-bullous congenital ichthyosiform erythroderma (CIE), where she has shown that aliphatic hydrocarbon accumulation is associated with ichthyosis; and b) Chanarin-Dorfman Syndrome (CDS, neutral lipid storage disease), a multisystem disorder, including ichthyosis, that is associated with abnormal fatty acid metabolism. In both diseases the basic defect will be sought in cultured cell lines established from these patients. CIE is of general interest because it suggests for the first time that alkanes may have a previously unrecognized role in mammalian cell function, while CDS is important because it promises to open up a relatively unexplored field of lipid metabolism, namely that of intracellular triglycerides.
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