The prostate gland is the most common site of neoplasia in aging men, and there are ongoing controversies pertaining to the molecular roles of stromal and epithelial cells in benign prostate hyperplasia (BPH) and cancer. Throughout their lifetimes, American men have a 1/6 chance of being diagnosed with prostate cancer and 90% of men over the age of 80 have symptomatic BPH leading to significant urinary track complications [1,2]. The genetic and environmental factors contributing to prostate disease, however, are poorly understood, and there are large gaps in our understanding of prostate tissue turnover and the rates of cellular replacement, and how differences in the rate at which cells are replaced impacts prostate disease initiation and progression. The rate at which prostate cells are created and replaced impact a person's risk of disease initiation and the rate of disease progression, and our preliminary data suggests that there are vast differences in prostate tissue turnover between individuals. Thus, an accurate understanding of prostate tissue turnover has the high potential to challenge existing paradigms of prostate function and prostate disease initiation, enable new experimental approaches to identify and characterize prostate epithelial stem cell pools, and re-define our current assumptions of tissue turnover in the prostate. Our central hypothesis is that prostate tissue has a more rapid turnover than seminal vesicle tissue, and that during BPH there is new cell formation in the prostate stroma leading to more rapid turnover of prostate epithelia.
The long term goal of this project is to elucidate the rate of tissue turnover in human prostate and seminal vesicle tissues, and to determine whether such differences in 14C content can 1) enable mechanistic studies to understand prostate tissue homeostasis and stem cell function, 2) to understand the stromal vs. epithelial origins of prostatic hyperplasia; and 3) be utilized to develop genetic clinical parameters that correlate with rates of cellular replacement. The objectives of this proposal are to determine the differences in genomic DNA 14C content between prostate zones, stroma vs. epithelia, and to optimize cell fractionation approaches to analyze specific prostatic cell types, including prostate stem cells.
