Nuclear Hormone Receptor in Intestinal Biology

肠道生物学中的核激素受体

基本信息

批准号：
7409096
负责人：
RAYMOND N. DUBOIS
金额：
$ 30.94万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7409096
关键词：
APC gene Abbreviations Address Adenomatous Polyposis Coli Adverse effects Affect Agonist Animal Model Anti-Inflammatory Agents Anti-inflammatory Antidiabetic Drugs Apoptosis Apoptotic Attenuated Azoxymethane Binding Biology Brain Cardiovascular system Cell Death Cell Differentiation Induction Cell Survival Cessation of life Chemopreventive Agent Cholesterol Class Clinical Treatment Clinical Trials Colon Carcinoma Colorectal Colorectal Cancer Combined Modality Therapy Complex Conflict (Psychology)Country Cultured Cells Data Developed Countries Development Digestive System Disorders Dinoprostone Disease Disease Progression Dominant-Negative Mutation Drug Delivery Systems Drug Receptors Dyslipidemias Enzymes Epithelial Epithelial Cell Proliferation Epithelial Cells Equilibrium Fatty Acids GW 501516 GW 7845 Gene Targeting Genes Glucose Growth Health Homeostasis Human Immediate-Early Genes In Vitro Individual Intestinal Cancer Intestinal Polyps Intestines Knowledge Laboratories Large Intestine Carcinoma Lead Ligands Malignant Epithelial Cell Malignant Neoplasms Measures Mediating Metabolism Missense Mutation Modeling Molecular Morbidity - disease rate Mus Non-Steroidal Anti-Inflammatory Agents Nuclear Nuclear Hormone Receptors Nuclear Orphan Receptor Nuclear Receptors Numbers Obesity Orphan PTGS2 gene Pathogenesis Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase III Clinical Trials Play Prevention Preventive Process Prostaglandin E Receptor Prostaglandin-Endoperoxide Synthase Protein Isoforms Receptor Cell Receptor Gene Regulation Regulatory Pathway Reporting Research Personnel Resistance Risk Role Signal Pathway Standards of Weights and Measures Testing Therapeutic Intervention Toxic effect Transactivation Transcriptional Activation Translational Research Treatment Protocols Tumor Suppressor Proteins Tumor Tissue Up-Regulation Xenograft procedure adenoma angiogenesis antitumor agent cancer cell carcinogenesis caspase-3 cell growth cell type cyclooxygenase 1 cyclooxygenase 2 design diabetic dosage gastrointestinal improved in vivo inhibitor/antagonist member mortality neoplastic neoplastic cell novel novel strategies oxidation polyposis programs receptor research clinical testing research study response tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): There are several molecular signaling pathways involved in the regulation of intestinal homeostasis and epithelial differentiation that are important in a number of digestive diseases. Colorectal cancer is one such disease and is a major health concern in this country. One group of compounds found to decrease the risk of colorectal cancer is non-steroidal anti-inflammatory drugs (NSAIDs). However, prolonged use of some of these agents is associated with unacceptable side effects (cardiovascular and gastrointestinal). Thus, it is crucial to develop more effective preventive measures with minimal toxicity and maximum benefit. Peroxisome proliferator-activated receptors (PPARs) are potential targets for chemopreventive agents. There are three PPAR isoforms, PPARa, PPARd, and PPAR?, which belong to the nuclear hormone receptor superfamily. Preliminary data indicates that a PPARd agonist promotes intestinal adenoma growth, increases tumor cell survival and induces angiogenesis. Since at least one PPARd agonist is currently under clinical evaluation for treatment of dyslipidemias and obesity, our results raise serious concerns about the use of these agents in people at high risk for colorectal cancer. Our preliminary data also indicate that activation of PPARd inhibits the ability of PPAR? to induce tumor cell death in vitro. We postulate that inhibition of PPARd may restore the ability of PPAR? agonists to induce apoptosis in vivo. We have recently identified a nuclear receptor NR4A2 which is a novel PGE2-regulated gene. NR4A2 is a nuclear receptor known to be involved in regulating brain function. We found that NR4A2 is elevated in human colorectal cancers and mediates the PGE2-induced activation of PPARd transcriptional activity by directly interacting with PPARd. However, the mechanisms by which NR4A2 modulates PPARd transcriptional activity during colorectal carcinogenesis are not clear. We propose the following specific aims to investigate these problems: 1) investigate mechanisms by which PPARd accelerates intestinal polyp growth and characterize PPARd target genes that control tumor growth; 2) characterize the role of PPARd in modulating the antitumor effects of PPAR? in colorectal cancer; and 3) delineate the mechanisms by which other nuclear receptors such as NR4A2 regulate PPARd transactivation. The results of the experiments proposed here may lead to the design of novel approaches for prevention and/or treatment of colorectal cancer.

描述（由申请人提供）：有几种分子信号传导途径涉及肠道稳态和上皮分化的调节，这在许多消化系统疾病中很重要。结直肠癌就是这样一种疾病，是这个国家的一个主要健康问题。一组被发现可以降低结直肠癌风险的化合物是非甾体抗炎药 (NSAID)。然而，长期使用其中一些药物会产生不可接受的副作用（心血管和胃肠道）。因此，制定更有效、毒性最小、效益最大的预防措施至关重要。过氧化物酶体增殖物激活受体（PPAR）是化学预防剂的潜在靶点。 PPAR 共有三种亚型：PPARa、PPARd 和 PPAR?，属于核激素受体超家族。初步数据表明 PPARd 激动剂可促进肠腺瘤生长、增加肿瘤细胞存活并诱导血管生成。由于目前至少有一种 PPARd 激动剂正在接受治疗血脂异常和肥胖症的临床评估，因此我们的结果引起了人们对在结直肠癌高危人群中使用这些药物的严重担忧。我们的初步数据还表明，PPARd 的激活会抑制 PPAR? 的能力？在体外诱导肿瘤细胞死亡。我们推测抑制PPARd可能会恢复PPAR的能力？激动剂诱导体内细胞凋亡。我们最近发现了一种核受体 NR4A2，它是一种新型的 PGE2 调节基因。 NR4A2 是一种已知参与调节大脑功能的核受体。我们发现 NR4A2 在人类结直肠癌中升高，并通过直接与 PPARd 相互作用介导 PGE2 诱导的 PPARd 转录活性激活。然而，NR4A2 在结直肠癌发生过程中调节 PPARd 转录活性的机制尚不清楚。我们提出以下具体目标来研究这些问题：1）研究PPARd加速肠息肉生长的机制并表征控制肿瘤生长的PPARd靶基因； 2) 描述 PPARd 在调节 PPAR 抗肿瘤作用中的作用？结直肠癌； 3) 描述其他核受体（例如 NR4A2）调节 PPARd 反式激活的机制。这里提出的实验结果可能会导致设计预防和/或治疗结直肠癌的新方法。