Impact of Cox‐2 on estrogen receptor beta action in prostate epithelial cells

Cox™2 对前列腺上皮细胞雌激素受体 β 作用的影响

基本信息

批准号：
10002345
负责人：
Donald B DeFranco
金额：
$ 21.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-22 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002345
关键词：
3-Dimensional Ablation Acute Adherens Junction Affect Affinity Aging Androgen Receptor Anti-Inflammatory Agents Apoptosis Benign Prostatic Hypertrophy Biological Markers Cell Line Cell physiology ChIP-seq Chronic Clinical Trials Clinical effectiveness Code Combination Drug Therapy Data Development Disease E-Cadherin Effectiveness Enzymes Epithelial Cell Junction Epithelial Cell Proliferation Epithelial Cells Estrogen Receptor beta Formalin Gene Expression Gene Expression Profile Homeostasis Human Inflammation Inflammatory Knockout Mice Laboratories Lead Ligands Measures Mediating Mediator of activation protein Metabolic MicroRNAs Modality Modeling Molecular New Agents Non-Steroidal Anti-Inflammatory Agents Outcome Oxidoreductase Pathway interactions Patients Pharmaceutical Preparations Pharmacology Prevention Production Prostate Prostatic Proteins Rattus Regulation Reporting Research Rodent Model Rofecoxib Signal Transduction Stanolone Steroid biosynthesis Symptoms System Testing Testosterone Tetanus Helper Peptide Tight Junctions Tissues Transcript Transfection Transforming Growth Factors Universities Untranslated RNA Up-Regulation androgenic celecoxib claudin-1 protein cyclooxygenase 2 cytokine drug action genetic signature genome-wide inhibitor/antagonist insight lower urinary tract symptoms men novel marker overexpression predicting response programs protective effect protein expression protein function response small hairpin RNA three dimensional cell culture transcriptome transcriptome sequencing

项目摘要

Project Summary: Prostatic inflammation is a common feature of symptomatic benign prostatic hyperplasia (BPH) and may alter epithelial cell proliferation and tissue homeostasis in BPH through cytokine induction of proinflammatory signaling mediators such as cyclooxygenase-2 (Cox-2). Cox-2 is overexpressed in luminal epithelial cells of BPH tissue but predominantly in regions of chronic inflammation. One clinical trial reported only a short-term benefit of a Cox-2 inhibitor (i.e. nonsteroidal anti-inflammatory agents [NSAIDs] such as rofecoxib) in reducing LUTS symptoms when combined with a 5AR inhibitor. The mechanism responsible for the limited clinical effectiveness of Cox-2 inhibition is not known. In the human BPH-1 prostate epithelial cell line (which expresses high basal levels of Cox-2), pharmacologic or molecular ablation of Cox-2 expression limits the protective effects of ERß through selective disruptions in steroidogenic enzyme expression leading to a reduced production of ERß ligands from testosterone. We therefore hypothesize that the limited effectiveness of NSAIDs in current BPH clinical trials is due to disruptions in prostatic steroidogenic pathways that generate ligands for the tissue protective ERß. Four Aims are proposed to test this hypothesis: Aim 1 will determine the impact of Cox-2 on ERß ligand production in PrECs. Aim 2 will identify genome-wide basal and ERß-regulated gene expression patterns influenced by acute or long-term adaptive responses to Cox-2 overexpression in PrECs. Aim 3 will identify the impact of Cox-2 and ERß on targets relevant to polarized epithelial cell function in 3- dimensional cultures of PrECs and ERß knockout mice. Aim 4 will determine the impact of Cox-2 on ERß signaling in human prostate explants and a rodent model of prostatic inflammation

项目概要：前列腺炎症是有症状的良性前列腺增生 (BPH) 的常见特征，可能会改变通过细胞因子诱导促炎作用来维持 BPH 中的上皮细胞增殖和组织稳态信号传导介质如环氧合酶-2 (Cox-2) 在管腔上皮细胞中过度表达。 BPH 组织，但主要出现在慢性炎症区域。一项临床试验仅报告了短期症状。 Cox-2 抑制剂（即非甾体类抗炎药 [NSAID]，如罗非考昔）在减少与 5AR 抑制剂联合使用时出现 LUTS 症状的机制有限。 Cox-2 抑制作用在人类 BPH-1 前列腺上皮细胞系（其中）中的有效性尚不清楚。表达高基础水平的 Cox-2），Cox-2 表达的药理学或分子消融限制了 ERß 通过选择性破坏类固醇生成酶的表达来发挥保护作用，从而导致因此，我们追求的是有限的有效性。当前 BPH 临床试验中非甾体抗炎药的使用是由于前列腺类固醇生成途径的破坏，从而产生组织保护性 ERß 的配体被提出来检验这一假设：目标 1 将确定 Cox-2 对 PrEC 中 ERß 配体产生的影响目标 2 将鉴定全基因组基础和 ERß 调节。基因表达模式受 Cox-2 过度表达的急性或长期适应性反应的影响 PrEC 目标 3 将确定 Cox-2 和 ERß 对与极化上皮细胞功能相关的靶标的影响在 PrEC 和 ERß 敲除小鼠的 3 维培养中，Aim 4 将确定 Cox-2 对 ERß 的影响。人类前列腺外植体和前列腺炎症啮齿动物模型中的信号传导