Chemopreventive signaling pathways

化学预防信号通路

基本信息

批准号：
8220784
负责人：
E. AUBREY THOMPSON
金额：
$ 7.75万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-03 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8220784
关键词：
2,4-thiazolidinedione Aberrant crypt foci Adverse effects Agonist Animals Attenuated Azoxymethane Calcineurin Calcineurin inhibitor Cancerous Chemopreventive Agent Clinical Data Colon Colon Carcinoma Cyclosporine Data Down-Regulation Epithelial Cells Epithelium FDA approved Family Future Gene Targeting Genes Genetic Genetic Transcription Genomics Goals Growth Heart Diseases Human Individual Informatics Knockout Mice Lesion Ligands Link Measures Mediating Mining Molecular Molecular Mechanisms of Action Mus Nodal Nuclear Receptors PPAR gamma PTGS2 gene Pathway interactions Peroxisome Proliferation Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphotransferases Pre-Clinical Model Process Property Receptor Activation Resistance Risk Saturated Fatty Acids Signal Pathway Signal Transduction Solutions Staging Systems Biology Tars Tenuate Testing Thiazolidinediones Work base cancer cell cancer chemoprevention cancer prevention carcinogenesis cardiovascular risk factor cell motility cohort colon cancer cell line colon carcinogenesis functional genomics in vivo neoplastic pre-clinical receptor small hairpin RNA therapeutic target tool transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Peroxisome proliferation-activated receptor-gamma 1 (PPAR?) is expressed at very high levels in colonic epithelial cells. Activation of this receptor by thiazolidinedione (TZD) drugs inhibits formation of pre-neoplastic aberrant crypt foci (ACF) in pre-clinical models of sporadic colon cancer. Humans who have large numbers of ACF are at risk for colon cancer, and the pre- clinical data suggest that activation of PPAR? might reduce the burden of ACF in humans who are at risk for colon cancer. However, recent data linking TZDs to cardiovascular risk make it unlikely that any TZD will ever be used for colon cancer chemoprevention in humans. There is therefore a pressing need to figure out how to take advantage of the chemopreventive potential of PPAR? while by passing potential deleterious side effects. Our solution is to use PPAR? as a tool to identify genomic pathways that are involved in suppression of transformed growth of early stage colon cancer cells. These pathways can then be developed as chemopreventive targets downstream of PPAR?. As proof-of-concept, we have used a systems biology approach to identify calcineurin as a nodal PPAR? target that controls the activity of the NFATc family of transcription factors. PPAR? induces an endogenous calcineurin inhibitor (DSCR1), which inhibits calcineurin, leading to inhibition of NFATc activity and subsequent downregulation of key NFATc target genes involved in invasion (COX2) and proliferation (c-MYC). Calcineurin is the product of several FDA-approved drugs which we will use to test the hypothesis that calcineurin is a nodal effector of a PPAR?-regulated pathway that controls invasion and proliferation of early stage colon cancer cells (Specific Aim 1). We will determine if genetic and pharmacological inhibition of calcineurin blocks ACF formation in azoxymethane-treated mice (Specific Aim 2). Finally, we will mine our genomic data to identify other PPAR?-regulated pathways that are linked to transformation and are targets of FDA-approved drugs. These pathways will be validated and evaluated for inhibition of proliferation and/or invasion in culture, with the view of testing their chemopreventive efficacy in vivo as part of our future goals.

描述（由申请人提供）：在结肠上皮细胞中，过氧化物酶体增殖激活的受体伽马1（PPAR？）在非常高的水平上表达。噻唑烷二酮（TZD）药物激活该受体会抑制在散发性结肠癌的临床前模型中形成的肿瘤前异常隐窝灶（ACF）。拥有大量ACF的人有结肠癌的风险，并且临床数据表明PPAR的激活？可能会减轻患有结肠癌风险的人类ACF的负担。但是，最近将TZD与心血管风险联系起来的数据使得任何TZD都不可能用于人类的结肠癌化学预防。因此，迫切需要弄清楚如何利用PPAR的化学预防潜力？通过传递潜在的有害副作用。我们的解决方案是使用PPAR？作为识别参与抑制早期结肠癌细胞转化生长的基因组途径的工具。然后，这些途径可以作为PPAR下游的化学预防靶标发展。作为概念验证，我们使用了系统生物学方法来识别钙调神经酶为淋巴结PPAR？控制NFATC转录因子家族活性的目标。 ppar？诱导内源性钙调蛋白抑制剂（DSCR1），该抑制剂抑制钙调蛋白，导致抑制NFATC活性，并随后下调参与侵袭（COX2）和增殖的关键NFATC靶基因和增殖（C-Myc）。钙调蛋白是几种FDA批准的药物的产物，我们将用来检验钙调神经酶是PPAR？调节途径的淋巴结效应子的假设，该途径控制着早期阶段结肠癌细胞的侵袭和增殖（特定目标1）。我们将确定钙氧甲烷处理的小鼠中钙调神经酶阻滞的遗传学和药理抑制是否形成了ACF的形成（特定的目标2）。最后，我们将挖掘我们的基因组数据，以识别与转化有关的其他PPAR？调节的途径，并且是FDA批准的药物的靶标。这些途径将经过验证和评估，以抑制培养物中的增殖和/或侵袭，并将其作为我们未来目标的一部分测试其体内化学预防功效。