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

描述(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。病理情况，如胰腺炎，已被认为与其中一个途径配体Sonic Hedgehog的表达和该途径的激活有关。Hedgehog途径下游的主要转录调节因子是Gli转录因子。Sonic Hedgehog也表达胰腺上皮瘤或Panin，这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活性不仅局限于间充质，而且也存在于上皮细胞中。在上皮细胞中，Gli1转录因子以不依赖于Hedgehog的方式激活。同样，在胰腺炎中，上皮Gli活性似乎是组织修复所必需的。这项建议的目的是了解Gli活性在胰腺疾病不同细胞亚群中的作用。在第一个目标中，我们将对Gli1在胰腺炎和组织修复中的表达和功能进行详细的表征。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下游效应分子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，目前该通路的新抑制剂正在临床上用于治疗基底细胞癌和髓母细胞瘤。目前可用的抑制剂在Smoothens(一种转导Hedgehog信号的跨膜蛋白)水平上阻断了这一途径。因此，这些抑制剂对以Hedgehog配体非依赖方式调节的Gli活性没有影响，也不能抑制Gli活性。此外，最近的证据表明，在Smoothens水平上的抑制与Smoothens突变形式的出现有关，这些突变形式对药物不再敏感。这项提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：尽管有几项研究讨论了Hedgehog信号在胰腺癌发生中的不同方面，但在这一点上，我们不知道该通路的激活是否在胰腺癌发生中是一个限制性的和必需的事件。这项建议的首要目标是了解Hedgehog抑制是否在胰腺癌治疗中具有潜在的治疗效果，以及如何针对这种疾病。由于Hedgehog信号被报道在胰腺癌中介导肿瘤-间质相互作用，我们将研究间质反馈到肿瘤的性质，以期找到新的治疗靶点。 与公共卫生相关：胰腺癌是一种可怕的疾病，预后非常糟糕。它构成了美国癌症死亡的第四大原因，其年死亡率相当于诊断率。迫切需要针对这种疾病的新的治疗选择，这些选择很可能是对这种疾病生物学的新见解的结果。Hedgehog信号通路与包括胰腺在内的几个器官的癌症有关。该途径的抑制剂目前正用于基底细胞癌的临床治疗。尽管有几项研究从不同的方面阐述了Hedgehog信号在胰腺癌发生中的作用，但目前我们还不知道该通路的激活是否在胰腺癌的发生中是一个限制性的和必需的事件。我们的研究旨在了解Hedgehog信号通路如何促进胰腺癌的发生，以及它是否会成为治疗这种疾病的有前途的靶点。

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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a horrific disease with a very dismal prognosis. It constitutes the fourth leading cause of cancer death in the US, and its yearly mortality equals the diagnosis rate. Novel therapeutic options for this disease are sorely needed, and they are likely to result from new insights on the biology of this disease. The Hedgehog signaling pathway involved in cancer of several organs, including the pancreas. Inhibitors of the pathway are currently in clinical therapy for basal cell carcinoma. 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. Our studies aim at understanding how the Hedgehog signaling pathway promotes pancreatic carcinogenesis, and whether it would constitute a promising therapeutic target for this disease.