Transgenic Mouse Model for Human Prostate Hyperplasia

Lavrovsky, Yan

Abstract

The proposed research is designed to generate a transgenic mouse model for prostatic hyperplasia in old age. Unlike man and dog, the rodent prostate does not continue to grow during aging. Immunolocalization of the androgen receptor in the rat and dog prostate has shown that while in the rat the receptor is localized in both epithelial and stromal cells of the prostate, in the dog it is exclusively localized in the stromal cells. Studies with prostatic tissues from old rats and dogs revealed that the stromal androgen receptor in the dog does not show any age- dependent decline. Additionally, in the case of old rats a block in the conversion of the basal to columnar epithelial cells was observed. It has already been established that epithelial cells of the prostate are stimulated by both the androgen and growth factors and that the paracrine growth factors are produced by the stromal tissue through androgenic stimulation. Based on the above findings l propose that the age-dependent enlargement of the prostate in the dog is due to continued androgenic stimulation of the stromal cells and the high level of growth factors produced from these stromal cells stimulate prostatic growth. This situation can be mimicked in the rodent by a targeted overexpression of the androgen receptor in the prostatic stromal cells of the transgenic mouse. We will use the keratinocyte growth factor gene promoter to target additional copies of the androgen receptor transgene with a histidine tag. The transgenic animals will be evaluated for prostatic hypertrophy through standard histological examination and the cell- specific production of the androgen receptor will be determined by immunohistochemistry. This transgenic mouse will provide the desired animal model for testing and development of appropriate therapeutic agents for prostatic hyperplasia during old age.