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.
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.
|Austin, David C; Strand, Douglas W; Love, Harold L et al. (2016) NF-ÎºB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance. Prostate 76:1004-18|
|Austin, David C; Strand, Douglas W; Love, Harold L et al. (2016) NF-ÎºB and androgen receptor variant expression correlate with human BPH progression. Prostate 76:491-511|
|Grabowska, Magdalena M; Kelly, Stephen M; Reese, Amy L et al. (2016) Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia. Endocrinology 157:1094-109|
|DeGraff, David J; Grabowska, Magdalena M; Case, Tom C et al. (2014) FOXA1 deletion in luminal epithelium causes prostatic hyperplasia and alteration of differentiated phenotype. Lab Invest 94:726-39|
|Lin-Tsai, Opal; Clark, Peter E; Miller, Nicole L et al. (2014) Surgical intervention for symptomatic benign prostatic hyperplasia is correlated with expression of the AP-1 transcription factor network. Prostate 74:669-79|
|Yu, X; Cates, J M; Morrissey, C et al. (2014) SOX2 expression in the developing, adult, as well as, diseased prostate. Prostate Cancer Prostatic Dis 17:301-9|
|Moad, Mohammad; Pal, Deepali; Hepburn, Anastasia C et al. (2013) A novel model of urinary tract differentiation, tissue regeneration, and disease: reprogramming human prostate and bladder cells into induced pluripotent stem cells. Eur Urol 64:753-61|
|Strand, Douglas W; DeGraff, David J; Jiang, Ming et al. (2013) Deficiency in metabolic regulators PPARÎ³ and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration. Am J Pathol 182:449-59|
|Strand, D W; Jiang, M; Murphy, T A et al. (2012) PPARÎ³ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation. Cell Death Dis 3:e361|
|Wang, Hongbo; Jiang, Ming; Cui, Hongmei et al. (2012) The stress response mediator ATF3 represses androgen signaling by binding the androgen receptor. Mol Cell Biol 32:3190-202|
Showing the most recent 10 out of 19 publications