The long term goals of our research are to understand the biochemical processes by which androgens and related hormones affect the prostate, seminal vesicles, and other target organs and also to provide molecular bases for treatment of abnormal growth of hormone sensitive and insensitive organs, such as benign prostate hyperplasia (BPH) and prostatic cancers.
The specific aims for the next 5 year period are: (1). To study the structure and functions of human and rat receptors for 5-androstene-3beta, 17beta-diol (5A-diol). This study includes characterization of receptors for 5A-diol, cloning of their cDNAs, and production of poly- and monoclonal antibodies to the receptors. (2). To study orphan receptors whose cDNAs we have isolated in the past or will be found during the isolation of cDNAs for the 5A-diol receptors. Poly- and monoclonal antibodies to the orphan receptors will be produced. We will also screen potential ligands (new hormones?) for orphan receptors. (3). To analyze mutation in androgen receptor (AR) genes in androgen- sensitive and insensitive prostate cancer cells and to identif AR sequences/domain structures and cellular factors that are important in the modulation of the transcriptional activity and intracellular recycling/replenishment of AR in prostate cells. Androgens including 5A-diol has unique effects in many male and female target organs and can also regulate the growth of androgen or estrogen sensitive tumors. The study of the structures and mutations of ARs is essential in understanding the abnormality in androgen actions. Since the functions of ARs may be modulated by cellular protein factors, identification and characterization of these factors may be important in understanding wholly how gene expression is positively or negatively modulated by androgens. 5A-diol may act by binding to a new receptor. Antagonists of 5A-diol binding to the receptor may have therapeutic values in traeating cancer and other disorders associated with 5A-diol.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK037694-06
Application #
3236730
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1986-07-01
Project End
1994-06-30
Budget Start
1991-09-30
Budget End
1992-06-30
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Kokontis, J; Takakura, K; Hay, N et al. (1994) Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res 54:1566-73
Liao, S (1994) Androgen action: molecular mechanism and medical application. J Formos Med Assoc 93:741-51
Song, C; Kokontis, J M; Hiipakka, R A et al. (1994) Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc Natl Acad Sci U S A 91:10809-13
Nakada, S Y; di Sant'Agnese, P A; Moynes, R A et al. (1993) The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Res 53:1967-70
Horie, K; Takakura, K; Imai, K et al. (1992) Immunohistochemical localization of androgen receptor in the human endometrium, decidua, placenta and pathological conditions of the endometrium. Hum Reprod 7:1461-6
Horie, K; Takakura, K; Fujiwara, H et al. (1992) Immunohistochemical localization of androgen receptor in the human ovary throughout the menstrual cycle in relation to oestrogen and progesterone receptor expression. Hum Reprod 7:184-90
Trifiro, M; Gottlieb, B; Pinsky, L et al. (1991) The 56/58 kDa androgen-binding protein in male genital skin fibroblasts with a deleted androgen receptor gene. Mol Cell Endocrinol 75:37-47
Kokontis, J; Ito, K; Hiipakka, R A et al. (1991) Expression and function of normal and LNCaP androgen receptors in androgen-insensitive human prostatic cancer cells. Altered hormone and antihormone specificity in gene transactivation. Receptor 1:271-9
Ris-Stalpers, C; Trifiro, M A; Kuiper, G G et al. (1991) Substitution of aspartic acid-686 by histidine or asparagine in the human androgen receptor leads to a functionally inactive protein with altered hormone-binding characteristics. Mol Endocrinol 5:1562-9
Kokontis, J; Liao, S; Chang, C (1991) Transcriptional activation by TR3 receptor, a member of the steroid receptor superfamily. Receptor 1:261-70

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