Chemopreventive signaling pathways

化学预防信号通路

基本信息

批准号：
8041164
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 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8041164
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）：过氧化物酶体增殖激活受体-γ 1 (PPAR?) 在结肠上皮细胞中表达水平非常高。在散发性结肠癌的临床前模型中，噻唑烷二酮 (TZD) 药物激活该受体可抑制肿瘤前异常隐窝病灶 (ACF) 的形成。拥有大量 ACF 的人有患结肠癌的风险，临床前数据表明 PPAR 的激活？可能会减轻有结肠癌风险的人类的 ACF 负担。然而，最近将 TZD 与心血管风险联系起来的数据表明，任何 TZD 都不可能用于人类结肠癌的化学预防。因此，迫切需要弄清楚如何利用 PPAR 的化学预防潜力？同时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。然后可以将这些途径开发为 PPAR? 下游的化学预防靶点。作为概念验证，我们使用系统生物学方法将钙调神经磷酸酶鉴定为节点 PPAR？控制 NFATc 转录因子家族活性的靶标。过氧化物酶体活化受体？诱导内源性钙调磷酸酶抑制剂 (DSCR1)，该抑制剂抑制钙调磷酸酶，从而抑制 NFATc 活性，并随后下调参与侵袭 (COX2) 和增殖 (c-MYC) 的关键 NFATc 靶基因。钙调磷酸酶是 FDA 批准的几种药物的产物，我们将用这些药物来检验以下假设：钙调磷酸酶是 PPAR 调节途径的节点效应物，该途径控制早期结肠癌细胞的侵袭和增殖（具体目标 1）。我们将确定钙调神经磷酸酶的遗传和药理学抑制是否会阻止氧化偶氮甲烷处理的小鼠中 ACF 的形成（具体目标 2）。最后，我们将挖掘我们的基因组数据，以确定与转化相关的其他 PPAR？调节途径，并且是 FDA 批准药物的目标。这些途径将在培养物中进行增殖和/或侵袭抑制的验证和评估，以测试其体内化学预防功效，作为我们未来目标的一部分。