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

描述（由申请人提供）：无论是在发育过程中还是在成年器官中，胰腺中的Hedgehog信号通路都是沉默的。病理状况，如胰腺炎，已经与通路配体之一Sonic Hedgehog的表达和通路的激活有关。Hedgehog通路的主要下游转录介质是Gli转录因子。Sonic Hedgehog基因也表达胰腺上皮瘤变（Pancreatic Epithelial Neoplasia, PanIN），这是胰腺癌最常见的前体病变。有强有力的证据表明，由肿瘤上皮细胞产生的Sonic Hedgehog基因对周围的间充质细胞（如成纤维细胞）具有旁分泌作用。另一方面，Gli活性并不局限于间质室，它也存在于上皮细胞中。在上皮细胞中，Gli1转录因子以不依赖刺猬的方式被激活。类似地，在胰腺炎中，上皮Gli活性似乎是组织修复所必需的。这是本建议的目的是了解Gli活性在胰腺疾病的不同细胞室中的作用。在第一篇文章中，我们将详细描述Gli1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，目前正在临床测试该通路的新抑制剂，用于治疗基底细胞癌和成神经管细胞瘤。目前可用的抑制剂在Smoothened水平上阻断通路，Smoothened是一种传递Hedgehog信号的跨膜蛋白。因此，这些抑制剂不影响以刺猬配体独立方式调节的Gli活性，它们不能抑制Gli活性。此外，最近的证据表明，Smoothened水平的抑制作用与Smoothened突变形式的出现有关，这些突变形式对药物不再敏感。本建议的长期目标是设计新的策略来抑制胰腺癌中的Gli活性。意义：虽然有几项研究探讨了胰腺癌发生过程中Hedgehog信号传导的不同方面，但目前我们还不知道该通路的激活是否是胰腺癌发生过程中的限制和必需事件。这项提议的总体目标是了解Hedgehog抑制是否在治疗胰腺癌中具有潜在的治疗效果，以及如何靶向这种疾病。由于有报道称Hedgehog信号在胰腺癌中介导肿瘤-基质相互作用，我们将研究基质对肿瘤反馈的性质，以确定新的治疗靶点。

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.