Impact of age on altered steroidogenesis and estrogen receptor activation in benign prostatic hyperplasia progression

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Project Summary/Abstract Candidate: My overall career goal is to become an independent investigator and leader in an aging related field focused on urologic diseases, especially lower urinary tract dysfunction (LUTD). Benign prostatic hyperplasia (BPH) is a disease that primarily affects aging men and manifests as urinary dysfunction. However, the etiology of the disease is complex and multifactorial and the impact of aging on the hormone environment is often not considered in current research. The overarching goal of my work is to examine the effects of aging on sex steroid hormones that contribute to the development of disease and identify biomarkers relevant to disease progression and treatment efficacy. The goal of this K01 career development proposal is to provide me with the research experience and training needed to become an independent investigator and leader in the field. My training will be targeted to three key areas: 1) molecular modeling of aging and disease, 2) identification and analysis of peripheral biomarkers, and 3) epigenetic modifiers of the aging steroid hormone environment. This research experience combined with the mentoring from leading experts at the University of Wisconsin – Madison will uniquely position me for a successful independent research career. Research: Benign prostatic hyperplasia (BPH) impacts 50% of men in their 50s but dramatically increases to 90% of men in their 80s with annual treatment costs $4 billion. One consequence of aging in males is altered steroid hormone synthesis and metabolism that leads to elevated levels of circulating estrogens. Estrogen signaling through estrogen receptors (ER) within the prostate regulate prostate tissue homeostasis with ERα associated with proliferation and ERβ with apoptosis. Current BPH treatments target the biosynthesis of androgens with little consideration for androgen conversion to ER ligands. I hypothesize that selective ER modulators (SERMs) can reestablish ERα:ERβ homeostasis through ERβ activation and reverse the impact of ERα-mediated proliferation on BPH progression in the aging male. The critical elements of this hypothesis will be tested in the following specific aims: Aim 1: Determine the impact of age-related changes in steroidogenic enzymes required for ERβ ligand production on prostate proliferation in vitro and in vivo. Aim 2: Examine the effect of aging on the epigenetic regulation of steroid hormone metabolism and activity. Aim 3: Evaluate the effectiveness of SERMs to limit hyperplasia in the aging prostate. The work proposed in these aims is designed to identify potential peripheral biomarkers to aid in assessing and stratifying BPH patients with age-associated hormone driven hyperplasia. This will allow for the development of novel combination pharmacotherapies that would enhance the clinical efficacy of current drug treatments.