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Molecular mechanism of FGF10 signaling in pancreatic development

FGF10信号在胰腺发育中的分子机制

基本信息

批准号：
7455199
负责人：
JAN JENSEN
金额：
$ 26.26万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2009-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The molecular mechanism of FGF10 signaling in the pancreas is not understood. FGF10 controls pancreatic epithelial cell division as well as differentiation. In absence of FGF10 (fgflO -/- mice), the pancreas fails to form and is arrested at the early budding stage. In the presence of increased levels of FGF10 (pPDX10-FGF10FLAG mice) the pancreatic epithelium maintains an increased level of proliferation, and becomes arrested in an undifferentiated state. The latter effect can be attributed to increased levels of Notch signaling. We found that Jaggedl and Jagged2, Notch ligands, previously uncharacterized in the developing pancreas, may account for this. This mechanism precedes the later involvement of Notch in selection of pancreatic terminal fates. In this proposal we will address the mechanistic basis of FGFlO-signaling in pancreatic development, and investigate how this signaling mechanism may control downstream target genes. We have identified the Ets-protein family as a plausible target for FGF10 phosphorylation, and through an evaluation of all members of this family by several exclusion criteria, we have found that the Etv-subfamily is involved in FGF10 signaling. We will here characterize the role of select members of the Etv-subfamily in pancreatic cell differentiation and during pancreatic progenitor cell expansion. We will also address these as targets of FGFlO-induced MARK phosphorylation and as regulators of FGF10 target gene expression in pancreatic progenitors. To do this, we will perform in-vitro, and in-vivo assays of gene function, including transgenic and targeted mutation strategies. This work is important in relation to the generation of a cell replacement source for Diabetes.

描述（由申请人提供）：胰腺中 FGF10 信号传导的分子机制尚不清楚。 FGF10 控制胰腺上皮细胞分裂和分化。在缺乏 FGF10 的情况下（fgfl0 -/- 小鼠），胰腺无法形成并在早期萌芽阶段停滞。在 FGF10 水平升高的情况下（pPDX10-FGF10FLAG 小鼠），胰腺上皮细胞的增殖水平保持升高，并停滞在未分化状态。后一种效应可归因于 Notch 信号传导水平的增加。我们发现 Jagged1 和 Jagged2、Notch 配体（以前在发育中的胰腺中未表征）可能解释了这一点。这种机制先于Notch后来参与胰腺终末命运的选择。在该提案中，我们将解决胰腺发育中FGF10信号传导的机制基础，并研究该信号传导机制如何控制下游靶基因。我们已将 Ets 蛋白家族鉴定为 FGF10 磷酸化的合理靶标，并通过几个排除标准对该家族的所有成员进行评估，我们发现 Etv 亚家族参与 FGF10 信号转导。我们将在这里描述 Etv 亚家族的选定成员在胰腺细胞分化和胰腺祖细胞扩增过程中的作用。我们还将把它们作为FGF10诱导的MARK磷酸化的靶标和作为胰腺祖细胞中FGF10靶基因表达的调节剂。为此，我们将进行基因功能的体外和体内测定，包括转基因和靶向突变策略。这项工作对于糖尿病细胞替代源的产生非常重要。