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

胰腺中的 Gli 活性：炎症、组织修复和癌症

• 批准号: 8658023
• 负责人: Marina Pasca Di Magliano
• 金额: $ 29.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658023
• 关键词: Address; Adult; Affect; Appearance; Basal cell carcinoma; Binding; Biology; Cancer Etiology; Cells; Cessation of life; Clinic; Clinical; Colon; Data; Development; Diagnosis; Disease; Employee Strikes; Epithelial; Epithelial Cells; Epithelium; Erinaceidae; Event; Family; Feedback; Fibroblasts; Figs - dietary; Gastrointestinal tract structure; Gene Targeting; Goals; Inflammation; Inflammatory; Inflammatory Response; Integral Membrane Protein; Interleukin-6; Intestines; Lesion; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mammals; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Mutation; Nature; Neoplasms; Organ; Outcome; Pancreas; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Process; Relapse; Reporting; Role; Scheme; Shapes; Source; Syndrome; Testing; Tissues; Treatment Efficacy; autocrine; cancer therapy; carcinogenesis; chemotherapy; colon carcinogenesis; cytokine; human SMO protein; human disease; inhibitor/antagonist; insight; interest; medulloblastoma; mortality; mouse model; mutant; neoplastic cell; new therapeutic target; novel therapeutics; outcome forecast; paracrine; pre-clinical; public health relevance; receptor; response; smoothened signaling pathway; therapeutic target; tissue repair; transcription factor; tumor; tumor growth; tumor microenvironment; tumorigenesis

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.

描述（由申请人提供）：在发育和成人器官期间，刺猬信号通路在胰腺中都是无声的。诸如胰腺炎之类的病理状况与途径配体，声波刺猬的表达和途径激活有关。刺猬途径的主要下游转录介质是GLI转录因子。 Sonic刺猬还表达胰腺上皮瘤或潘宁，这是胰腺癌最常见的前体病变。有强有力的证据表明，肿瘤上皮细胞在间质起源（例如成纤维细胞）周围细胞上产生的声波刺猬的旁分泌作用。另一方面，GLI活性不仅限于间充质室，但也存在于上皮细胞中。在上皮细胞中，Gli1转录因子以刺猬独立的方式被激活。同样，在胰腺炎中，组织修复似乎需要上皮GLI活性。该提议的目的是了解Gli活性在胰腺疾病中不同细胞室中的作用。在第一个目标中，我们将对胰腺炎和组织修复中GLI1的表达和功能进行详细的表征。我们的第二个目标是研究Panin形成期间的GLI表达和功能。最后，在第三个目标中，我们将解决GLI在胰腺炎和胰腺癌中的下游效应子的作用。刺猬信号通路是一个有吸引力的治疗靶标，目前在基础细胞癌和髓母细胞瘤的诊所中测试了该途径的新抑制剂。当前可用的抑制剂阻止了平滑水平的途径，这是一种转导刺猬信号的跨膜蛋白。因此，这些抑制剂对以刺猬独立的方式调节的GLI活性没有影响，并且不能抑制GLI活性。此外，最近的证据表明，平滑水平的抑制与不再对药物敏感的平滑形式的出现相关。该提案的长期目标是制定新的策略来抑制胰腺癌的GLI活性。意义：尽管几项研究已经解决了胰腺癌发生中刺猬信号的不同方面，但此时，我们尚未知道该途径的激活是否是胰腺癌发生中的限制和所需事件。该提案的总体目标是了解刺猬抑制是否在治疗胰腺癌以及如何靶向这种疾病方面具有潜在的治疗功效。由于据报道，刺猬信号传导介导胰腺癌中的肿瘤 - 细胞瘤相互作用，因此我们将研究基质对肿瘤的反馈性质，其目标是鉴定新的治疗靶标。