ANDROGEN REGULATION OF HUMAN SEBACEOUS GLANDS

Project: Research project

Description

The overall goal of this mentored research program is to provide the P.I. with the opportunity to develop further the cognitive, technical and interpretive skills required to pursue her career goal of combining clinical practice with basic research. The specific goal of the experiments proposed is to elucidate androgens' role in controlling the development and differentiation of the sebaceous gland (SG). Androgens are thought to modulate sebum production by the SG and, thereby, to contribute to the development of acne vulgaris, a prevalent disease associated with significant physical and psychological morbidity. Understanding the mechanisms regulating SG growth and lipogenesis by androgens is essential for developing rationale strategies to control sebum production and acne. In order to characterize these mechanisms we have established an organotypic culture (histoculture) system for propagating intact human SG in the presence and absence of their native dermal fibroblasts. Manipulating this system, using androgens, inhibitors of androgen metabolizing enzymes and growth factors, and tissue specific ribozyme constructs to prevent selectively the translation of individual transcripts, will enable us to test the following hypotheses: i) Conversion of testosterone to dihydrotestosterone by type 1 5a-reductase in fibroblasts and sebocytes is an obligatory step in the modulation of SG growth and lipid production and; ii) Growth and lipid production of SG is regulated by paracrine interactions between growth factors and androgens. We will determine if androgens act on the SG only directly, or also indirectly via dermal fibroblasts. Should fibroblasts prove to be involved in mediating some actions of androgens on SG growth and lipid production, we will determine if growth factors generated by fibroblasts, specifically epidermal growth factor, insulin-like growth factor-I and keratinocyte growth factor, are involved in this process. Endpoints for assessing sebaceous gland growth will include, incorporation of 3H thymidine, Ki-67 immunocytochemistry and histology. Lipogenesis will be determined using incorporation of 14C-acetate into lipids. Pharmacological inhibitors of each of the enzymes involved in the metabolism of androgens, and which are known to be expressed in human SG, will be used to identify the role of individual C-19 steroids in modulating specific aspects of growth and lipid production by SG. Results on the role of 1 5alpha-reductase, androgen receptor and growth factor of interest will be confirmed by transfecting sebocytes and dermal fibroblasts with a construct containing a novel triple ribozyme, driven by tissue-specific promoters, which will selectively cleave transcript for the enzyme, receptor or peptide.
StatusFinished
Effective start/end date12/15/9611/30/01

Funding

  • National Institutes of Health
  • National Institutes of Health: $112,579.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $112,579.00

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Sebaceous Glands
Androgens
Fibroblasts
Lipids
Growth
Sebum
Intercellular Signaling Peptides and Proteins
Catalytic RNA
Lipogenesis
Acne Vulgaris
Skin
Oxidoreductases
Fibroblast Growth Factor 7
Peptide Receptors
Fibroblast Growth Factors
Dihydrotestosterone
Androgen Receptors
Enzyme Inhibitors
Enzymes
Insulin-Like Growth Factor I