Benign prostatic hyperplasia (BPH) is an extremely common disease of older men which leads to morbidity by obstructing urine outflow. There is a considerable body of evidence implicating increased estrogen, in conjunction with androgens, as an underlying factor in the etiology of BPH, but the mechanism by which these hormonal alterations lead to BPH is unclear. The investigators have shown increased expression of FGF7 and FGF2 in BPH that is correlated with epithelial and stromal proliferation, respectively. The role of androgens and estrogens in controlling FGF7 and FGF2 production in the prostate is either controversial or unknown. They have also shown that paracrine factors secreted by prostatic epithelial cells can stimulate production of FGFs by prostatic stromal cells. For FGF7 this paracrine factor is IL- 1alpha. FGF 17, which can increase proliferation of fibroblastic cells, is also expressed by prostatic epithelial cells. Their hypothesis is that increases in estrogen, in combination with androgen, can synergistically stimulate FGF2 and FGF7 production by stromal cells in BPH, which can be further stimulated by local, epithelial derived paracrine factors that both induce FGF production and enhance proliferation of FGF producing stromal cells. They propose two Specific Aims:
Specific Aim 1 : Control of FGF7 and FGF2 expression by androgens and estrogens: Using primary cultures of human stromal cell they will assess the effect of androgens, estrogens, and paracrine epithelial factors, alone or in combination, on FGF7 and FGF2 production. They will then determine the mechanism by which FGF protein expression is increased in response to the inducing factors. Finally, they will evaluate the effects of androgens and estrogens on FGF production and proliferation using an in vivo model system in which human tissue is implanted in scid/hpg mice.
Specific Aim 2 : Control of FGF7 and FGF2 expression by paracrine epithelial factors: Their first goal is to correlate expression of IL- Ialpha with expression of FGF7 to test their hypothesis that FGF7 production can be driven by IL- 1alpha. In vivo they will derive a transgenic mouse line that expresses IL- 1alpha at high concentrations in the prostate and determine whether there is induction of FGF7 expression in parallel with hyperplasia of the prostate. The second goal is to identify the epithelial derived paracrine factor(s) which induces FGF2 production by stromal cells. Their final goal is to define the role of FGF 17 as an epithelial derived paracrine inducer of stromal cell proliferation.
