Fibroblast Growth Factor Regulation in the Pancreas

胰腺中成纤维细胞生长因子的调节

• 批准号: 7635748
• 负责人: Sam R Holmstrom
• 金额: $ 5.17万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635748
• 关键词: Address; Cells; Cholecystokinin; Cyclic AMP; Data; Digestion; Disease; Endocrine; Enzymes; Exocrine pancreas; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Fluids and Secretions; Gallbladder; Gene Expression; Goals; Hormonal; Hormones; In Vitro; Individual; Inflammatory; Intervention; Knockout Mice; Lead; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Membrane; Metabolism; Methods; Mitogen-Activated Protein Kinases; Mus; Nuclear Receptors; Nutrient; Pain; Pancreas; Pancreatic Diseases; Pancreatic Exocrine Secretion; Pancreatic enzyme; Pancreatitis; Pathology; Pathway interactions; Pharmacological Treatment; Proteomics; Receptor Signaling; Regulation; Role; Secretin; Signal Pathway; Signal Transduction; Testing; base; blood glucose regulation; hormone regulation; in vivo; mouse fibroblast growth factor 15; novel therapeutics; outcome forecast; pancreatic juice; receptor; response; uptake

DESCRIPTION (provided by applicant): The exocrine portion of the pancreas regulates digestion and is an important modulator of nutrient uptake. Abnormalities in exocrine pancreas function can lead to serious conditions such as pancreatitis and pancreatic cancer. The hormonal control of the exocrine pancreas has been well-studied in regards to cholecystokinin (CCK)-induced stimulation of the digestive enzyme secretions. Our recent studies show that fibroblast growth factor 15 (FGF15) is a secreted endocrine hormone that promotes gallbladder filling and opposes CCK-induced contraction of the gallbladder (9). Based on our preliminary data, our hypothesis is that FGF15 acts as a broader anti-CCK signal and counter-regulates exocrine pancreas secretions. FGF15 signaling through FGF receptors also functions together with nuclear receptors to regulate transcriptional responses in the liver (19). Since the pancreas expresses these same nuclear receptors, we predict that the same pathways will be also be operative. The long term goals of this project are to explore the role of FGF15 in regulating exocrine pancreas function by both rapid and transcriptional mechanisms. In the first aim, I will address whether FGF15 regulates exocrine pancreas digestive enzyme secretion by rapid mechanisms. This will be accomplished by testing the ability of FGF15 to oppose the pancreas secretions induced by various stimulants in vivo. In addition, this aim will determine the ability of FGF15 to directly oppose enzyme secretions from isolated pancreas cells in vitro. I will also use proteomic analysis of pancreatic secretions to evaluate differences in WT and previously-generated mice that lack FGF15. In the second aim, I will examine the intracellular signaling and transcriptional responses involved in FGF15 regulation of exocrine pancreas function. This will involve exploring the role of the intracellular messenger, cyclic AMP, as well as Mitogen-Activated Protein Kinase (MAPK) pathways in mediating FGF15 responses using both in vivo and in vitro approaches. Finally, I will investigate whether FGF15 regulates gene expression in the exocrine pancreas using QPCR methods. Several mouse lines with deficient expression of individual components of nuclear receptor or FGF signaling will be used for this analysis. FGF receptor signaling is implicated in the pancreatitis and exocrine pancreatic cancer pathologies (23), yet treatments for these conditions are still lacking. Therefore, understanding the hormonal regulation of exocrine pancreas function by FGF15 may yield new therapeutic avenues with high potential for pharmacological intervention by targeting membrane receptors.

描述（由申请人提供）：胰腺的外分泌部分调节消化，是养分吸收的重要调节剂。外分泌胰腺功能的异常会导致严重的疾病，例如胰腺炎和胰腺癌。关于胆囊动蛋白（CCK）诱导的消化酶分泌的刺激，外分泌胰腺的激素控制已得到充分研究。我们最近的研究表明，成纤维细胞生长因子15（FGF15）是一种分泌的内分泌激素，可促进胆囊填充并反对CCK引起的胆囊收缩（9）。根据我们的初步数据，我们的假设是FGF15充当更广泛的抗CCK信号，并反调节外分泌胰腺分泌。 FGF15通过FGF受体的信号传导还与核受体一起起作用，以调节肝脏中的转录反应（19）。由于胰腺表达了这些相同的核受体，因此我们预测相同的途径也将是可操作的。该项目的长期目标是探索FGF15在快速和转录机制中调节外分泌胰腺功能中的作用。在第一个目标中，我将通过快速机制来解决FGF15是否调节外分泌胰腺消化酶的分泌。这将通过测试FGF15反对体内各种兴奋剂引起的胰腺分泌的能力来实现。此外，该目标将决定FGF15直接在体外反对分离的胰腺细胞中的酶分泌的能力。我还将使用胰腺分泌物的蛋白质组学分析来评估缺乏FGF15的WT和先前生成的小鼠的差异。在第二个目标中，我将检查涉及FGF15外分泌胰腺功能的细胞内信号传导和转录反应。这将涉及探索细胞内信使，环状AMP以及有丝分裂原激活的蛋白激酶（MAPK）途径在使用体内和体外方法介导FGF15反应中的作用。最后，我将使用QPCR方法调查FGF15是否调节外分泌胰腺中的基因表达。该分析将使用几种核受体或FGF信号单个成分表达不足的小鼠系。 FGF受体信号传导与胰腺炎和外分泌胰腺癌病理有关（23），但仍缺乏治疗这些疾病。因此，了解FGF15对外分泌胰腺功能的激素调节可能会产生新的治疗途径，该途径通过靶向膜受体，具有很高的药理干预潜力。