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

项目摘要：前列腺注射是症状性良性前列腺增生（BPH）的常见特征，可能会改变通过促炎性诱导的细胞因子诱导，BPH中的上皮细胞增殖和组织稳态信号介质（例如环氧合酶2）（COX-2）。 COX-2在腔内上皮细胞中过表达 BPH组织，但主要用于慢性感染区域。一项临床试验仅报告了短期 COX-2抑制剂（即诸如Rofecoxib之类的非甾体抗炎剂[NSAIDS]）的好处在还原 LUTS符号与5AR抑制剂结合使用。负责有限临床的机制 COX-2抑制的有效性尚不清楚。在人类BPH-1前列腺上皮细胞系中表达高基本水平的COX-2），药物结肠或分子烧蚀Cox-2表达限制了 ERß通过选择性破坏类固醇生成酶表达的保护作用，导致A 减少了睾丸激素的Erß配体产生。因此，我们假设有限的有效性当前BPH临床试验中的NSAID是由于产生的前列腺类固醇生成途径的破坏组织保护的配体。提出了四个目标来检验这一假设：AIM 1将确定 COX-2对ERß配体产生的影响。 AIM 2将识别全基因组基本和ERß调节的受急性或长期自适应反应COX-2过表达影响的基因表达模式先驱。 AIM 3将确定COX-2和ERß对与极化上皮细胞功能相关的目标的影响在PREC和ERß基因敲除小鼠的三维培养物中。 AIM 4将确定COX-2对ERß的影响人类前列腺外植体中的信号传导和前列腺注射的啮齿动物模型