Inflammation is very common in the adult prostate and it is associated with the development of benign prostatic hyperplasia (BPH). We do not know what the primary causes of inflammation in the prostate are, and we do not understand how it promotes prostate disease in men, but proposed mechanisms include released molecules from inflammatory cells that promote prostatic growth, and increases in steroid hormone levels made within the prostate in response to inflammation. The lack of a complete model system that mimics all aspects of human BPH is a key reason for this knowledge gap. Among the pathological features of advanced and highly symptomatic BPH are characteristic proliferative ringlet structures of intraepithelial hyperplasia termed ?microglandular hyperplasia?. This terminology arises from the histological structures of small ?micro? glands forming within epithelial nodules. Unlike other models of inflammation-induced hyperplasia of the rodent prostate, our recently published Toxoplasma gondii model of prostatic inflammation induces this histological patterning that is observed in humans, and is associated with symptoms similar to human BPH including increased urinary frequency and decreased urinary volumes. This suggests that mechanisms that induce both cell proliferation and tissue patterning might connect inflammation to hyperplasia and prostate disease, and our T. gondii model, which induces both components, would allow us to test this idea. Our hypothesis is that T. gondii-induced chronic prostatic inflammation promotes hyperplasia by promoting cytokine-mediated growth factor signaling and de novo biosynthesis of estrogen and testosterone. Prostatic hyperplasia in humans is associated with increased activity of IL-1 and IGF-1. Therefore in our first aim, we propose to determine if chronic inflammation induced by T. gondii infection induces proliferation in the prostate by activating the IL-1 to IGF-1 pathway. In this aim, we will employ a combination of molecular and pharmacological methods to assess the in vivo expression and production of inflammation-induced IL-1 and IGF-1 associated with hyperplasia and urinary symptoms in T. gondii-infected prostates. In the second aim, we will determine if T. gondii -induced microglandular hyperplasia results from induction of de novo steroid synthesis in the prostate, and we will assess the role of the druggable targets CYP17A1 and androgen and estrogen receptors in this process. We will also investigate the mechanism of how T. gondii induces steroid synthesis. Finally, we will determine if CYP17A1-driven steroid synthesis is associated with inflammation and microglandular hyperplasia in human BPH. It is known that de novo synthesis of androgen and estrogen occurs in prostates with BPH. We will finish with a prospective analysis of prostate tissue from men with BPH compared to non-diseased men to determine if inflammation, hyperplasia, and cytokine and growth factor expression, correlate with steroid synthesis in the prostate and lower urinary tract symptoms characteristic of BPH in men.
Inflammation of the prostate gland is suspected to play a critical role in the development of benign prostatic hyperplasia and resulting lower urinary tract symptoms. The proposed research will investigate the mechanisms of how inflammation promotes microglandular hyperplasia and associated lower urinary symptoms in the mouse prostate using the Toxoplasma gondii model of hyperplasia, the only known model that promotes inflammation, microglandular hyperplasia, and lower urinary tract symptoms.
