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成纤维细胞生长因子（FGF）信号通路在胰岛中的生理作用。胰岛是一个功能单位，以受调节的方式分泌胰岛素、胰高血糖素和其他激素，这些过程受到广泛的细胞间（旁分泌）通讯的调节。胰岛β细胞功能障碍是II型糖尿病的一个标志，了解这些细胞在整个胰岛中的功能将增强对疾病过程的建模。我们的初步数据和其他人的结果表明 FGF 和 FGF 受体 (FGFR) 在 β 细胞中合成。使用显性失活受体表达扰动小鼠胰腺中的这一信号通路已被证明可以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，通过多种机制引发细胞信号传导，包括释放内部 Ca2+ 储备和激活磷脂酰肌醇 3-激酶 (PI3K)。 FGF 在许多不同的细胞类型中发挥不同的作用，包括增殖、细胞存活和血管生成。提出了三个具体目标来检查胰岛中这种多样化的信号传导途径：1）确定旁分泌刺激（FGF、胰岛素、胰高血糖素、生长抑素、ATP）在葡萄糖刺激的胰岛 Ca2+ 振荡传播中的作用。 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 β 细胞 PI3K/Akt 通路以及这种激活是否会提高细胞存活率。第一个目标是使用双通道微流体装置以葡萄糖梯度处理 FGF 刺激的胰岛，并结合定量荧光显微镜观察代谢和 Ca2+ 反应。更具体地说，我们将确定内部 Ca2+ 储存的刺激释放是否会改变葡萄糖刺激的代谢反应。第二个具体目标是检查β细胞分泌FGF所涉及的细胞运输途径，并确定其分泌在葡萄糖刺激期间是否上调。第三个具体目标是使用显性失活受体亚型来检查 PI3K 在 β 细胞中的激活情况。 PI3K 和下游 Akt 的激活已被证明可以增强细胞存活率。这些研究将确定 FGFR 信号是否在 β 细胞中被激活，并参与维持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。初步证据表明成纤维细胞生长因子（FGF）可能参与了这种调节。这些研究将检验 FGF 是否参与调节胰岛素分泌，以及 FGF 是否增强胰岛素分泌 β 细胞的存活率。