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.

到第8个生命的第8个十年 其特征是前列腺过渡区（TZ）的组织质量显着增加。降低 尿路症状（LUTS）的特征是膀胱中的主要症状。近距离 这两个与生理相关的器官的接近性使我们探索了这样的假设 这些疾病的发展和进展可能在常见的病理状态下与 我们将其指定为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，包括前列腺在内的人体组织中积累了衰老细胞。这些 衰老细胞的功能改变了，包括增加促炎细胞因子的表达 改变相邻细胞的功能。我们的初步数据强烈支持了细胞的概念 衰老对BPH/LUTS有重大贡献。该提议的目的是表征 细胞衰老可以促进良性前列腺增生和 通过旁分泌作用和/或机械阻塞会导致膀胱变化。三个目标是 建议的。在AIM 1中，我们将确定衰老相关的细胞因子在BPH上皮中是否上调 如果它们的水平与其他衰老标记的水平相关，并表征了细胞因子和 BPH上皮和基质的上调的生长因子与该上皮（periacinar基质）相邻。 这个目的我们将在上皮衰老在BPH中的作用并得出A的作用来检验我们的假设 BPH/LUTS中潜在重要的细胞因子/生长因子的全面清单。在AIM 2中，我们将探索 使用我们小组开发的几种新型，高度可访问的模型来检查的效用 在上皮/基质相互作用的背景下，针对细胞生长和细胞表型的特定细胞因子。在 目标3我们将利用几个前列腺特异性的转基因小鼠模型来检查 前列腺炎性细胞因子的可能作用在诱导尿中的细胞改变中 通过旁分泌作用和/或机械阻塞与LUTS相关的膀胱。