I will study a molecular mechanism which regulates growth in the developing prostate ducts and determines how manipulations that increase or decrease the activity of this mechanism alter prostate development and influence the extent of growth. This study will provide new insights into potential mechanisms for abnormal growth, provide an animal model for BPH, and suggest new pharmacologic approaches to control prostate growth. Prostate development begins when urogenital sinus epithelium grows into the surrounding mesenchyme and initiates a sustained process of ductal growth and branching. Testosterone is a stimulus to ductal development. However, growth normally stops at a defined endpoint despite the continued presence of testosterone - indicating that other factors regulate the extent of growth. In several well-studied systems the Hox genes are dominant regulators of growth in development. Hox genes function as transcriptional regulators. Each Hox gene is expressed in a time and region specific manner and exerts a permissive overarching influence on cell proliferation and growth. The Hox genes are called the morphogenetic clock since time-dependent down-regulation arrests morphogenesis and caps the potential for further growth. I have found that the gene Hox-d13 is expressed in the ducts of the developing prostate. Expression down- regulates as morphogenesis is completed. Retinoic acid, a direct regulator of the Hox genes, inhibits Hox-d13 expression in the developing prostate. Ductal morphogenesis is inhibited and a stunted adult prostate ductal system results. I postulate that Hox-d13 expression regulates the extent of prostate ductal growth. I will use a quantitative assay for Hox-d13 expression, localization studies, and quantitative analysis of prostate ductal morphogenesis to examine the correlation of Hox-d13 expression with ductal growth in normal development. I will then determine the effect on prostate development of reversible inhibition of Hox-d13 expression by retinoic acid, loss of expression in (an existing) transgenic Hox-d13 """"""""knockout"""""""" mouse, and overexpression in a proposed transgenic animal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002426-03
Application #
2684034
Study Section
Special Emphasis Panel (SRC)
Program Officer
Bishop, Terry Rogers
Project Start
1996-04-26
Project End
2001-03-31
Budget Start
1998-06-26
Budget End
1999-03-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Lamm, Marilyn L; Catbagan, Winnie S; Laciak, Robert J et al. (2002) Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev Biol 249:349-66
Barnett, Daniel H; Huang, Hong-Ying; Wu, Xue-Ru et al. (2002) The human prostate expresses sonic hedgehog during fetal development. J Urol 168:2206-10
Lamm, M L; Podlasek, C A; Barnett, D H et al. (2001) Mesenchymal factor bone morphogenetic protein 4 restricts ductal budding and branching morphogenesis in the developing prostate. Dev Biol 232:301-14
Podlasek, C A; Seo, R M; Clemens, J Q et al. (1999) Hoxa-10 deficient male mice exhibit abnormal development of the accessory sex organs. Dev Dyn 214:1-12
Podlasek, C A; Barnett, D H; Clemens, J Q et al. (1999) Prostate development requires Sonic hedgehog expressed by the urogenital sinus epithelium. Dev Biol 209:28-39
Podlasek, C A; Clemens, J Q; Bushman, W (1999) Hoxa-13 gene mutation results in abnormal seminal vesicle and prostate development. J Urol 161:1655-61
Seo, R; McGuire, M; Chung, M et al. (1997) Inhibition of prostate ductal morphogenesis by retinoic acid. J Urol 158:931-5