A primary sebaceous cell monolayer culture system has been developed in which for the first time a high level of terminal differentiation and sebum formation can be reproducibly induced. This has been accomplished using rat preputial cells, by activation of peroxisome proliferator activated receptors (PPARs) in a chemical defined, serum free medium. These findings imply that sebum formation is transduced via PPARs and that the factors regulating sebocyte growth and differentiation can now be precisely defined. W propose studies of sebaceous cell physiology to do so.
Specific aim : 1)To measure sebocyte proliferation by 3H thymidine incorporatio and sebocyte differentiation by analysis of lipid staining cells and lipid-forming colonies (LFCs) to define the interactions among PPAR activators and other factors regulating sebocyte growth and development. Pharmacologic probes will be used in order to test the hypothesis about the biological effects of interactions among PPAR activators-ligands and retinoid X receptor (RXR)-ligands, factors such as retinoic acid receptor (RAR) ligands affecting RXR availability to form PPAR heterodimers, steroid hormones, the insulin/insulin like growth factor (IGF) system, and hormones signaling via other second messengers. 2) To use riboprobes and immunoprobes to test the hypothesis that sebocytes express specific PPAR, RXR, and RAR subtypes and isoforms. 3) To determine the factors regulating PPAR gene expression using riboprobes and immunoprobes. The hypotheses will be tested that PPAR ligand-activators and androgens increase sebocytes PPAR gene expression. The hypothesis will also be tested that PPARd is constitutively expressed and expression of other PPARS is developmentally regulated. The long term goals are to address specific basic issues in sebocyte developmental biology which have implication for the development of new therapies for acne vuglaris. These issues are equally important in providing a new primary cell culture, biological model system for examining interactions among factors regulating cell proliferation and differentiation, particularly in comparison to adipocyte and reporter construct model systems.
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