Paracrine Regulation of BPH Pathogenesis

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DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) is an important cause of orbidity in the adult male population and is the most common symptomatic tumor-like condition in humans. Clinically BPH results in urethral constriction with a consequent slowing of urinary flow rates and an inability to properly empty the urinary bladder. In the Western world BPH is not a life threatening condition. However, it is a condition with significant associated morbidity and consequent healthcare costs. BPH results in a variety of problems including nocturia, frequency, urgency and post-mictural dribbling and, more seriously it can cause renal insufficiency (with rising serum creatinine), frequent urinary tract infections and urosepsis due to insufficient urinary draining. For many decades the core of research into BPH has centered around androgen and estrogen signaling. These studies have given rise to the development of 51-reductase inhibitors such as finasteride and dutasteride. However these directions have not shown much recent progress in developing new approaches to improve the situation of patients. New concepts are sorely needed to move the field forwards. The central hypothesis of this proposal is that prostatic inflammation results in a profile of stromal changes which contribute to focal benign glandular expansion. The long term goal of this work is to identify pathways which can be co-targeted ether alone as a form of chemoprevention or along with current standard BPH therapies to provide safe and long term symptomatic relief. This proposal addresses a number of the high priority recommendations of the recently published NIDDK Prostate Research Strategic Plan including; the creation of new models; the development of an understanding of the signaling, interaction and crosstalk between multiple cell types in the prostate; and, the characterization of disease-relevant cellular pathways for potential therapeutic applications. The three specific aims in this proposal address interlocking aspects of BPH pathogenesis. The first aim looks at the effects of inflammatory cytokine expression on prostatic epithelial and stromal differentiation. The second aim examines the consequences of these changes in relation to the recruitment of bone marrow- derived cell populations and the contribution that these play in hyperplastic growth. The third aim examines the targeting of nuclear factor-kappa B as a strategy to influence BPH pathogenesis. PUBLIC HEALTH RELEVANCE: The root causes of benign prostatic hyperplasia (BPH) are unclear ut likely involve inflammation in the prostate. Current treatments aim to reduce androgenic stimulation and to relax prostatic smooth muscle. This project will investigate the potential of inflammatory responses to contribute to benign prostatic enlargement with a view to adding treatment options to either slow prostatic growth or relieve symptoms of BPH.