Nuclear Hormone Receptor in Intestinal Biology

描述（由申请人提供）：有几种分子信号通路参与调节肠道稳态和上皮分化，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，长期使用这些药物中的一些与不可接受的副作用（心血管和胃肠道）有关。因此，至关重要的是制定毒性最小、效益最大的更有效的预防措施。过氧化物酶体增殖物激活受体（PPARs）是化学预防剂的潜在靶点。有三种PPAR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价，因此我们的研究结果引起了对这些药物在结直肠癌高危人群中使用的严重关注。我们的初步数据还表明，激活的PPARd抑制的能力？以在体外诱导肿瘤细胞死亡。我们推测，抑制PPARd可能恢复的能力，过氧化物酶体增殖物激活受体？激动剂以在体内诱导细胞凋亡。我们最近发现了一个核受体NR 4A 2，这是一个新的PGE 2调节基因。NR 4A 2是已知参与调节脑功能的核受体。我们发现NR 4A 2在人结直肠癌中升高，并通过直接与PPARd相互作用介导PGE 2诱导的PPARd转录活性的激活。然而，NR 4A 2在结直肠癌发生过程中调节PPARd转录活性的机制尚不清楚。我们提出了以下具体目标，调查这些问题：1）调查机制，PPARd加速肠息肉的生长和PPARd的靶基因，控制肿瘤生长的特点; 2）特点的PPARd在调节抗肿瘤作用的PPARd？在结直肠癌中;和3）描绘其他核受体如NR 4A 2调节PPARd反式激活的机制。本文提出的实验结果可能会导致设计新的方法来预防和/或治疗结直肠癌。

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.