ANDROGEN REGULATION OF HUMAN SEBACEOUS GLANDS

Project: Research project

Project Details

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 date12/15/9611/30/97

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases

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