Mechanisms of Cytokine Induced Lower Urinary Track Pathology

描述（由申请人提供）：到第8个十年，大约80%的男性有良性前列腺增生（BPH）的证据，其特征是前列腺移行区（TZ）的组织质量显著增加。下尿路症状（LUTS）的特征在于膀胱中的主要症状。这两个生理相关器官的紧密接近使我们探索了这样一种假设，即这些疾病的发展和进展可能与我们指定为BPH/LUTS的常见病理状况相关。细胞衰老是一个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。这些衰老细胞具有改变的功能，包括增加促炎细胞因子的表达，其可以改变邻近细胞的功能。我们的初步数据强烈支持细胞衰老对BPH/LUTS有显著影响的概念。本提案的目的是表征细胞衰老可促进良性前列腺增生的发展并通过旁分泌效应和/或机械阻塞诱导膀胱变化的机制。提出了三个目标。在目的1中，我们将确定衰老相关的细胞因子是否在BPH上皮中上调，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BPH上皮和与该上皮相邻的基质（腺泡周围基质）中上调的细胞因子和生长因子。这个目标，我们将测试我们的假设，上皮细胞衰老的作用在BPH和推导出一个全面的列表中的潜在重要的细胞因子/生长因子在BPH/LUTS。在目标2中，我们将探索使用我们小组开发的几种新的，高度易处理的模型的实用性，以检查特定细胞因子对上皮/基质相互作用背景下的细胞生长和细胞表型的影响。在目标3中，我们将利用几种前列腺启动子特异性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