Fibroblast Growth Factor signaling in Pancreatic Islets

胰岛中的成纤维细胞生长因子信号传导

• 批准号: 7034870
• 负责人: JONATHAN V ROCHELEAU
• 金额: $ 10.26万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034870
• 关键词: adenosine triphosphate; biological signal transduction; calcium flux; fibroblast growth factor; glucagon; glucose metabolism; growth factor receptors; hormone regulation /control mechanism; insulin; laboratory mouse; microfluidics; pancreatic islet function; pancreatic islets; paracrine; phosphatidylinositol 3 kinase; secretion; somatostatin

DESCRIPTION (provided by applicant): The long term goal of these studies is to elucidate the physiological role of the fibroblast growth factor (FGF) signaling pathway in the pancreatic islet. The pancreatic islet is a functional unit that secretes insulin, glucagon and other hormones in a regulated manner, processes that are modulated by extensive cell-cell (paracrine) communication. Pancreatic islet beta-cell dysfunction is a hallmark of Type II diabetes, and understanding the function of these cells in the context of a whole islet will enhance modeling of the disease process. Our preliminary data and the results of others indicate that FGFs and FGF receptors (FGFRs) are synthesized in beta-cells. Perturbation of this signaling pathway in the mouse pancreas using dominant-negative receptor expression has been shown to modulate insulin secretion and resulted in a diabetic phenotype. Regulated secretion of FGF can activate receptor to cause cell signaling by a number of mechanisms, including the release of internal Ca2+-stores and the activation of phosphatidylinositol 3-kinase (PI3K). FGF has varied roles in many different cell types including proliferation, cell survival, and angiogenesis. Three specific aims have been proposed to examine this diverse signaling pathway in the pancreatic islet: 1) Determine the role of paracrine stimulation (FGF, insulin, glucagons, somatostatin, ATP) in the propagation of glucose-stimulated pancreatic islet Ca2+ oscillations. 2) Identify the subcellular route of fibroblast growth factor (FGF) secretion from pancreatic islet beta-cells. 3) Determine whether FGF activates the beta-cell PI3K/Akt pathway and whether this activation leads to enhanced cell survival. The first aim will use a two channel microfluidic device to treat FGF stimulated islets with a glucose gradient, in combination with quantitative fluorescence microscopy to observe the metabolic and Ca2+-responses. More specifically, we will determine whether stimulated release of internal Ca2+-stores modifies the glucose-stimulated metabolic response. The second specific aim will examine the cellular trafficking routes involved in FGF secretion from beta-cells and determine whether its secretion is up-regulated during glucose-stimulation. The third specific aim will use a dominant-negative receptor isoform to examine the activation of PI3K in beta-cells. Activation of PI3K and downstream Akt has been shown to enhance cell survival. These studies will determine whether FGFR signaling is activated in beta-cells, and involved in maintenance of glucose-stimulated insulin secretion. Lay language summary: The proposed work will examine the regulation of insulin secretion. Preliminary evidence shows that fibroblast growth factor (FGF) may be involved in this regulation. These studies will examine whether FGF is involved in regulating insulin secretion, and whether FGF enhances the survival of insulin secreting beta-cells.

描述（由申请人提供）： 这些研究的长期目标是阐明胰岛中成纤维细胞生长因子（FGF）信号通路的生理作用。胰岛是一个功能单位，以调节的方式分泌胰岛素，胰高血糖素和其他激素，这些过程受广泛的细胞细胞（旁分泌）通信调节的过程。胰岛β细胞功能障碍是II型糖尿病的标志，在整个胰岛的背景下，了解这些细胞的功能将增强疾病过程的建模。我们的初步数据以及其他结果表明FGF和FGF受体（FGFR）在β细胞中合成。使用显性阴性受体表达的小鼠胰腺中这种信号通路的扰动已显示可调节胰岛素分泌，并导致糖尿病表型。 FGF的调节分泌可以激活受体，以通过多种机制引起细胞信号传导，包括释放CA2+商店的释放以及磷脂酰肌醇3-激酶（PI3K）的激活。 FGF在许多不同的细胞类型中具有不同的作用，包括增殖，细胞存活和血管生成。已经提出了三个具体目的，以检查胰岛中的这种不同的信号传导途径：1）确定旁分泌刺激（FGF，胰岛素，葡萄糖，糖素，体重抑素，ATP）在葡萄糖刺激的胰岛胰岛含量ca2+振动中的作用。 2）确定胰岛β细胞分泌成纤维细胞生长因子（FGF）的亚细胞途径。 3）确定FGF是否激活了β细胞PI3K/AKT途径，以及这种激活是否导致细胞存活增强。第一个目标将使用两个通道的微流体装置与葡萄糖梯度一起处理FGF刺激的胰岛，并结合定量荧光显微镜，以观察代谢和Ca2+回答。更具体地说，我们将确定刺激的内部Ca2+商店的释放是否会改变葡萄糖刺激的代谢反应。第二个特定目的将检查β细胞中FGF分泌的细胞运输途径，并确定其分泌在葡萄糖刺激期间是否上调。第三个特定目的将使用显性阴性受体同工型检查β细胞中PI3K的激活。 PI3K和下游AKT的激活已显示可增强细胞存活。这些研究将确定FGFR信号是否在β细胞中激活，并参与葡萄糖刺激的胰岛素分泌。 外行语言摘要：拟议的工作将检查胰岛素分泌的调节。初步证据表明，该调节可能涉及成纤维细胞生长因子（FGF）。这些研究将检查FGF是否参与调节胰岛素分泌，以及FGF是否增强了胰岛素分泌β细胞的存活。