By the 8th decade of life approximately 80% of men have evidence of benign prostatic hyperplasia (BPH), which is characterized by markedly increased tissue mass in the transition zone (TZ) of the prostate. Lower urinary tract symptoms (LUTS) are characterized by primary symptoms in the urinary bladder. The close proximity of these two physiologically related organs has led us to explore the hypothesis that the development and progression of these conditions may be associated in a common pathological condition which we designate as BPH/LUTS. Cellular senescence is a process that limits the proliferation of human cells. Senescent cells accumulate in human tissues, including the prostate, with increasing age. These senescent cells have altered function, including increased expression of proinflammatory cytokines that can alter the function of adjacent cells. Our preliminary data strongly supports the concept that cellular senescence contributes significantly to BPH/LUTS. The goal of this proposal is to characterize the mechanisms by which cellular senescence can promote the development of benign prostatic hyperplasia and via paracrine effects and/or mechanical obstruction induce changes in the urinary bladder.
Three Aims are proposed.
In Aim 1 we will determine if senescence associated cytokines are upregulated in BPH epithelium and if their levels correlate with levels of other senescence markers and characterize the cytokines and growth factors upregulated in BPH epithelium and stroma adjacent to this epithelium (periacinar stroma).
This Aim we will both test our hypothesis regarding the role of epithelial senescence in BPH and derive a comprehensive list of potentially important cytokines/growth factors in BPH/LUTS.
In Aim 2 we will explore the utility of using several novel, highly tractable models developed by our group to examine the impact of specific cytokines on cell growth and cellular phenotype in the context of epithelial/stromal interactions.
In Aim 3 we will take advantage of several prostate promoter-specific transgenic mouse models to examine the possible role of inflammatory cytokines from the prostate gland in inducing cellular alterations in the urinary bladder associated with LUTS via paracrine effects and/or mechanical obstruction.
The vast majority of older men have benign prostatic hyperplasia, which is characterized by markedly increased tissue mass in the prostate. This growth of the prostate and associated changes in the bladder leads to urinary obstruction and lower urinary tract symptoms and causes considerable morbidity.The goal of this proposal is to understand the underlying cause of this disease in order to develop novel therapies.
|Zhang, Boyu; Kwon, Oh-Joon; Henry, Gervaise et al. (2016) Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor. Mol Cell 63:976-89|
|Vital, Paz; Castro, Patricia; Ittmann, Michael (2016) Oxidative stress promotes benign prostatic hyperplasia. Prostate 76:58-67|
|Vital, Paz; Castro, Patricia; Tsang, Susan et al. (2014) The senescence-associated secretory phenotype promotes benign prostatic hyperplasia. Am J Pathol 184:721-31|
|Kwon, Oh-Joon; Zhang, Li; Ittmann, Michael M et al. (2014) Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin. Proc Natl Acad Sci U S A 111:E592-600|