Chemopreventive signaling pathways

描述（由申请人提供）： 过氧化物酶体增殖激活受体-γ 1（PPAR？）在结肠上皮细胞中以非常高的水平表达。噻唑烷二酮（TZD）药物激活该受体可抑制散发性结肠癌临床前模型中肿瘤前异常隐窝病灶（ACF）的形成。有大量ACF的人有患结肠癌的风险，临床前数据表明，激活的过氧化物酶体增殖物激活受体？可能会减少结肠癌风险人群中ACF的负担。然而，最近的数据将TZD与心血管风险联系起来，使得任何TZD都不太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？作为鉴定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，这些途径可被开发为PPAR？下游的化学预防靶点。作为概念验证，我们已经使用了系统生物学的方法来确定钙调神经磷酸酶作为一个节点的过氧化物酶体激活受体？控制NFATc转录因子家族活性的靶点。PPAR？诱导内源性钙调磷酸酶抑制剂（DSCR 1），其抑制钙调磷酸酶，导致NFATc活性的抑制和随后参与侵袭（COX 2）和增殖（c-MYC）的关键NFATc靶基因的下调。钙调神经磷酸酶是几种FDA批准的药物的产物，我们将使用这些药物来检验钙调神经磷酸酶是PPAR？的淋巴结效应物的假设。调节途径，控制早期结肠癌细胞的侵袭和增殖（特异性目的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断氧化偶氮甲烷处理小鼠的ACF形成（具体目标2）。最后，我们将挖掘我们的基因组数据，以确定其他的过氧化物酶体增殖物激活受体？与转化相关的受调控途径，是FDA批准药物的靶点。这些途径将被验证和评估，以抑制增殖和/或入侵的文化，在体内测试其化学预防功效，作为我们未来目标的一部分。

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.