Mechanisms of Cytokine Induced Lower Urinary Track Pathology

到第八个十年，大约80%的男性有良性前列腺增生（BPH）的证据， 其特征在于前列腺移行区（TZ）中的组织质量显著增加。低 尿路症状（LUTS）的特征在于膀胱中的原发症状。收盘 这两个生理上相关的器官的接近使我们探索了这一假设， 这些病症的发展和进展可能与共同的病理学病症有关 我们称之为BPH/LUTS。细胞衰老是一个限制人类细胞增殖的过程， 细胞随着年龄的增长，衰老细胞在包括前列腺在内的人体组织中积累。这些 衰老细胞的功能改变，包括促炎细胞因子的表达增加， 改变相邻细胞的功能。我们的初步数据有力地支持了细胞的概念， 衰老对BPH/LUTS有显著影响。本提案的目标是描述 细胞衰老可促进良性前列腺增生发展的机制， 通过旁分泌效应和/或机械阻塞引起膀胱的变化。三个目标是 提出了在目标1中，我们将确定是否衰老相关的细胞因子在BPH上皮细胞中上调 以及它们的水平是否与其它衰老标志物的水平相关，并表征细胞因子， 生长因子在BPH上皮和与该上皮相邻的间质（腺泡周围间质）中上调。 我们将检验我们关于上皮衰老在BPH中的作用的假设， BPH/LUTS中潜在重要的细胞因子/生长因子的综合列表。在目标2中，我们将探索 使用我们小组开发的几种新颖的、高度易处理的模型来研究 在上皮/基质相互作用的背景下，特异性细胞因子对细胞生长和细胞表型的影响。在 目的3：我们将利用几种前列腺启动子特异性转基因小鼠模型， 前列腺炎性细胞因子在诱导泌尿系统细胞改变中的可能作用 通过旁分泌效应和/或机械性阻塞与LUTS相关的膀胱。

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.