Mechanisms of Cytokine Induced Lower Urinary Track Pathology

描述(由申请人提供)：到了第八个十年，大约80%的男性有良性前列腺增生症(BPH)的证据，其特征是前列腺移行区(TZ)组织质量显著增加。下尿路症状(LUTS)的特征是以膀胱为主要症状。这两个生理上相关的器官非常接近，这让我们探索了一种假设，即这些疾病的发生和发展可能与一种常见的病理情况有关，我们将其命名为BPH/LUTS。细胞衰老是限制人类细胞增殖的过程。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发生了变化，包括促炎细胞因子的表达增加，这些细胞因子可以改变邻近细胞的功能。我们的初步数据有力地支持了细胞衰老对BPH/LUTS有重要贡献的概念。本研究的目的是描述细胞衰老促进良性前列腺增生症的发展，并通过旁分泌效应和/或机械阻塞引起膀胱改变的机制。提出了三个目标。在目标1中，我们将确定衰老相关细胞因子是否在BPH上皮细胞中上调，以及它们的水平是否与其他衰老标志物的水平相关，并表征在BPH上皮细胞和与其相邻的间质(腺泡周围间质)中上调的细胞因子和生长因子。为了达到这个目的，我们将检验我们关于上皮细胞衰老在BPH中的作用的假说，并得出一个在BPH/LUTS中潜在重要的细胞因子/生长因子的综合清单。在目标2中，我们将探索使用我们团队开发的几个新的、高度易处理的模型来研究特定细胞因子在上皮/基质相互作用的背景下对细胞生长和细胞表型的影响。在目标3中，我们将利用几种特定于前列腺癌启动子的转基因小鼠模型来研究前列腺炎性细胞因子在诱导细胞改变中的可能作用。

DESCRIPTION (provided by applicant): 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 pro-inflammatory 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