Gli Activity in the Pancreas: Inflammation, Tissue Repair and Cancer

描述（由申请人提供）：Hedgehog信号通路在胰腺中是沉默的，无论是在发育过程中还是在成年器官中。病理条件，如胰腺炎已链接到表达的途径配体之一，刺猬，和激活的途径。Hedgehog途径的主要下游转录介质是Gli转录因子。Sonic Hedgehog也在胰腺上皮瘤变或PanIN中表达，PanIN是胰腺癌最常见的前驱病变。有强有力的证据表明，由肿瘤上皮细胞产生的Sonic Hedgehog对间充质来源的周围细胞如成纤维细胞具有旁分泌作用。另一方面，Gli活性并不局限于间充质隔室，它也存在于上皮细胞中。在上皮细胞中，Gli 1转录因子以Hedgehog独立的方式被激活。类似地，在胰腺炎中，上皮Gli活性似乎是组织修复所需的。本提案的目的是了解Gli活性在胰腺疾病中不同细胞区室中的作用。在第一个目标中，我们将详细描述Gli 1在胰腺炎和组织修复中的表达和功能。我们的第二个目标是研究Gli在PanIn形成过程中的表达和功能。最后，在第三个目标中，我们将讨论Gli下游效应物在胰腺炎和胰腺癌中的作用。Hedgehog信号通路是一个有吸引力的治疗靶点，并且该通路的新抑制剂目前正在基底细胞癌和髓母细胞瘤的临床中进行测试。目前可用的抑制剂在Smoothened的水平上阻断该途径，Smoothened是一种转导Hedgehog信号的跨膜蛋白。因此，这些抑制剂对以刺猬配体非依赖性方式调节的Gli活性没有影响，并且它们不能抑制Gli活性。此外，最近的证据表明，Smoothened水平的抑制与Smoothened突变形式的出现有关，这些突变形式不再对药物敏感。这项提案的长期目标是设计新的策略来抑制胰腺癌中的Gli活性。重要性：虽然一些研究已经解决了胰腺癌发生中Hedgehog信号传导的不同方面，但我们目前还不知道该途径的激活是否是胰腺癌发生中的限制性和必需事件。该提案的总体目标是了解Hedgehog抑制是否在胰腺癌治疗中具有潜在的治疗效果，以及如何靶向这种疾病。由于据报道Hedgehog信号转导介导胰腺癌中的肿瘤-间质相互作用，我们将研究间质对肿瘤反馈的性质，目的是确定新的治疗靶点。

DESCRIPTION (provided by applicant): The Hedgehog signaling pathway is silent in the pancreas, both during development and in the adult organ. Pathological conditions such as pancreatitis have been linked to expression of one of the pathway ligands, Sonic Hedgehog, and activation of the pathway. The main downstream transcriptional mediators of the Hedgehog pathway are Gli transcription factors. Sonic Hedgehog is also expressed Pancreatic Epithelial Neoplasia or PanIN, the most common precursor lesion to pancreatic cancer. There is strong evidence of a paracrine role of Sonic Hedgehog, produced by the tumor epithelial cells, on the surrounding cells of mesenchymal origin such as fibroblasts. On the other hand, Gli activity is not confined to the mesenchymal compartment, but it is also present in the epithelial cells. In the epithelial cells, the Gli1 transcription factor is activated in a Hedgehog-independent manner. Similarly, in pancreatitis, epithelial Gli activity appears to be required for tissue repair. It is the aim of this proposal to understand the role of Gli activity in the different cell compartment in pancreatic disease. In the First Aim, we will be performing a detailed characterization of the expression and function of Gli1 in pancreatitis and tissue repair. Our Second Aim will be to study Gli expression and function during PanIn formation. Finally, in the Third Aim, we will address the role of downstream effectors of Gli in pancreatitis and pancreatic cancer. The Hedgehog signaling pathway is an attractive therapeutic target and new inhibitors of the pathway are currently been tested in the clinic for Basal Cell carcinoma and medulloblastoma. The inhibitors that are currently available block the pathway at the level of Smoothened, a transmembrane protein that transduces the Hedgehog signal. Therefore, these inhibitors do not have an effect on Gli activity that is regulated in a Hedgehog-ligand independent manner, and they cannot inhibit Gli activity. Moreover, recent evidence has indicated that inhibition at the level of Smoothened is linked with the appearance of mutant forms of Smoothened that are no longer sensitive to the drug. The long-term goal of this proposal is to devise new strategies to inhibit Gli activity in pancreatic cancer. Significance: Although several studies have addressed different aspects of Hedgehog signaling in pancreatic carcinogenesis, we do not, at this point, know whether activation of this pathway is a limiting and required event in pancreatic carcinogenesis. The overarching goal of this proposal is understand whether Hedgehog inhibition has potential therapeutic efficacy in the treatment of pancreatic cancer, and how to target this disease. Since Hedgehog signaling is reported to mediate tumor-stroma interactions in pancreatic cancer, we will study the nature of the stromal feedback to the tumor with the goal to identify new therapeutic targets.