Mechanisms of Cytokine Induced Lower Urinary Track Pathology

细胞因子诱导下尿路病理学机制

• 批准号: 8566162
• 负责人: Michael M Ittmann
• 金额: $ 30.47万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-29 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566162
• 关键词: Age; Aging; Automobile Driving; Benign; Benign Prostatic Hypertrophy; Biological Models; Biology; Bladder; Bladder Urothelial Cell; Bladder Urothelium; Cell Aging; Cell Culture System; Cells; Data; Development; Disease; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Epithelium; Esthesia; Functional disorder; Goals; Growth; Growth Factor; Human; IL8 gene; Inflammatory; Instruction; Lasers; Lead; Life; Lower urinary tract; Mechanics; Messenger RNA; Microarray Analysis; Modeling; Morbidity - disease rate; Obstruction; Organ; Pathology; Phenotype; Play; Process; Prostate; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory Receptors; Severities; Stromal Cells; Symptoms; System; Testing; Tissues; Transgenic Mice; Urine; age related; base; cell growth; cytokine; human tissue; lower urinary tract symptoms; men; mouse model; novel; older men; oxidative DNA damage; paracrine; progenitor; promoter; reconstitution; senescence; stem; telomere; urinary

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.

到八岁的时候，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）的组织质量显着增加。降低 尿路症状 (LUTS) 的特征是膀胱的主要症状。关闭 这两个生理相关器官的接近使我们探索了这样的假设： 这些病症的发生和进展可能与常见的病理病症有关 我们将其称为 BPH/LUTS。细胞衰老是限制人类增殖的过程 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 衰老细胞的功能发生改变，包括促炎细胞因子的表达增加， 改变邻近细胞的功能。我们的初步数据强烈支持这样的概念：蜂窝 衰老对 BPH/LUTS 有显着影响。该提案的目标是描述 细胞衰老促进良性前列腺增生的机制 通过旁分泌作用和/或机械阻塞引起膀胱的变化。三个目标是 建议的。在目标 1 中，我们将确定 BPH 上皮中衰老相关细胞因子是否上调 如果它们的水平与其他衰老标志物的水平相关并表征细胞因子和 BPH 上皮和邻近该上皮的基质（腺泡周围基质）中生长因子上调。 为了这个目的，我们将检验我们关于上皮衰老在 BPH 中的作用的假设，并得出一个 BPH/LUTS 中潜在重要细胞因子/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且易于处理的模型来检查影响的效用 在上皮/基质相互作用的背景下，特定细胞因子对细胞生长和细胞表型的影响。在 目标 3 我们将利用几种前列腺启动子特异性转基因小鼠模型来检查 来自前列腺的炎症细胞因子在诱导尿细胞改变中的可能作用 膀胱通过旁分泌作用和/或机械性阻塞与 LUTS 相关。