Abstract

The long term objective of this proposal is to understand steroid hormone regulation of peptidergic and aminergic neuronal systems. Immediate aims are to determine the distribution of androgen receptors (AR) in brain, to describe the ontogeny of AR gene expression and determine whether AR colocalizes with other steroid hormone receptors (progesterone, glucocorticoid and estradiol). [3H]Dihydrotestosterone autoradiography will be combined with immunocytochemistry using receptor antibodies that are currently available and well characterized. In addition a modified method of dual immunohistochemistry will be utilized. Biological effects of androgen and other steroid hormones on neuronal functions will be determined by quantitative in situ hybridization assays of messenger RNA for various neuropeptides and neurotransmitter biosynthetic enzymes in peptidergic and aminergic neurons respectively. Initial studies will focus on steroid hormone regulation of neurons producing gonadotropin releasing hormone (GnRH), thyrotropin releasing hormone (TRH), growth hormone releasing factor (GRF) and tyrosine hydroxylase (TH). Using the same method, the effects of androgens and other steroid hormones on AR mRNA levels will be determined. Both testosterone and its nonaromatizable metabolite, dihydrotestosterone, will be administered to distinguish between the effects of androgen and estrogen. Emphasis will be on neurons in which multiple steroid hormone receptors colocalize in order to determine the interrelationships among various steroid hormone actions. Immunohistochemistry will be utilized in an investigation of the mechanism of nuclear translocation of AR using a series of recombinant androgen receptor deletion mutants expressed in COS cells and natural mutants in human genital skin fibroblasts from humans with the androgen insensitivity syndrome. Structural alterations of AR that influence nuclear localization will be correlated with changes in the transcriptional activation function of AR. It is anticipated that these studies will contribute to our understanding of steroid hormone actions in the regulation of brain function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS017479-09
Application #
3397603
Study Section
Reproductive Biology Study Section (REB)
Project Start
1982-09-01
Project End
1994-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Wong, C; Kelce, W R; Sar, M et al. (1995) Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide. J Biol Chem 270:19998-20003
Zhou, Z X; Sar, M; Simental, J A et al. (1994) A ligand-dependent bipartite nuclear targeting signal in the human androgen receptor. Requirement for the DNA-binding domain and modulation by NH2-terminal and carboxyl-terminal sequences. J Biol Chem 269:13115-23
Junker, J; Sommer, J R; Sar, M et al. (1994) Extended junctional sarcoplasmic reticulum of avian cardiac muscle contains functional ryanodine receptors. J Biol Chem 269:1627-34
Shughrue, P J; Sar, M; Stumpf, W E (1992) Progestin target cell distribution in forebrain and midbrain regions of the 8-day postnatal mouse brain. Endocrinology 130:3650-9
Kemppainen, J A; Lane, M V; Sar, M et al. (1992) Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation. Specificity for steroids and antihormones. J Biol Chem 267:968-74
Shughrue, P J; Stumpf, W E; Elger, W et al. (1991) Progestin receptor cells in mouse cerebral cortex during early postnatal development: a comparison with preoptic area and central hypothalamus using autoradiography with [125I]progestin. Brain Res Dev Brain Res 59:143-55
Simental, J A; Sar, M; Lane, M V et al. (1991) Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem 266:510-8
McGimsey, W C; Cidlowski, J A; Stumpf, W E et al. (1991) Immunocytochemical localization of the glucocorticoid receptor in rat brain, pituitary, liver, and thymus with two new polyclonal antipeptide antibodies. Endocrinology 129:3064-72
Shughrue, P J; Stumpf, W E; Elger, W et al. (1991) Progestin receptor cells in the 8-day-old male and female mouse cerebral cortex: autoradiographic evidence for a sexual dimorphism in target cell number. Endocrinology 128:87-95
Sar, M; Lubahn, D B; French, F S et al. (1990) Immunohistochemical localization of the androgen receptor in rat and human tissues. Endocrinology 127:3180-6

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