To provide insight into the normal pathway of androgen action during embryonic and, postembryonic life and into the mechanism by which impairments of androgen action can result in disease, experiments will be addressed to each of the three principal phases of androgen action - binding of androgen to the receptor, 5alpha-reduction of testosterone to dihydrotestosterone, and aromatization of androgen to estrogen. In regard to the androgen receptor, we will analyze the molecular defects in selected patients with mutations that impair receptor function, develop improved functional and genetic techniques for diagnosing and tracing the Inheritance of mutations of the androgen receptor, define the control elements that regulate expression of the androgen receptor gene, and Investigate the regulation of androgen receptor levels in different androgen target tissues. To provide insight into the role of dihydrotestosterone formation in androgen physiology, we will Investigate the mechanism by which dihydrotestosterone formation amplifies the androgen signal In vivo and in in vitro systems. To define the role of the estrogenic metabolites of androgen in androgen action, we analyze the nature of the start sites for aromatase in normal ovary and a normal tissue in which extraglandular estrogen is formed (brain) and study the mechanism of the control of tissue-specific gene expression in a testicular cell line in which the control of aromatase is derranged. In summary, we will utilize physiological, genetic, endocrinological, and molecular techniques for analysis of androgen action and its pathophysiology. These studies have direct relevance to human disease - both for common birth defects such as hypospadias and for impairment of sexual differentiation in the less common disorders of male pseudohermaphroditism due to androgen resistance.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Biochemical Endocrinology Study Section (BCE)
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University of Texas Sw Medical Center Dallas
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Lanzino, Marilena; Garofalo, Cecilia; Morelli, Catia et al. (2009) Insulin receptor substrate 1 modulates the transcriptional activity and the stability of androgen receptor in breast cancer cells. Breast Cancer Res Treat 115:297-306
McPhaul, Michael J (2008) Mechanisms of prostate cancer progression to androgen independence. Best Pract Res Clin Endocrinol Metab 22:373-88
Kohler, Birgit; Delezoide, Anne-Lise; Boizet-Bonhoure, Brigitte et al. (2007) Coexpression of Wilms'tumor suppressor 1 (WT1) and androgen receptor (AR) in the genital tract of human male embryos and regulation of AR promoter activity by WT1. J Mol Endocrinol 38:547-54
Pitteloud, Nelly; Meysing, Astrid; Quinton, Richard et al. (2006) Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol 254-255:60-9
Pitteloud, Nelly; Acierno Jr, James S; Meysing, Astrid U et al. (2005) Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 90:1317-22
Lanzino, Marilena; De Amicis, Francesca; McPhaul, Michael J et al. (2005) Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells. J Biol Chem 280:20421-30
Villegas, Jacob; McPhaul, Michael (2005) Establishment and culture of human skin fibroblasts. Curr Protoc Mol Biol Chapter 28:Unit 28.3
Pitteloud, Nelly; Villegas, Jacob; Dwyer, Andrew A et al. (2004) Acute stress masking the biochemical phenotype of partial androgen insensitivity syndrome in a patient with a novel mutation in the androgen receptor. J Clin Endocrinol Metab 89:1053-8
Unni, Emmanual; Sun, Shihua; Nan, Bicheng et al. (2004) Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence. Cancer Res 64:7156-68
Szebenyi, Gyorgyi; Morfini, Gerardo A; Babcock, Alyssa et al. (2003) Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40:41-52

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