TFG-Beta Isoform Signaling in Pancreatic Development

描述（由申请人提供）：我们研究的总体目标是 更好地了解控制胰腺发育的分子力， 谱系选择了解这些力量可以让我们更好地对待这种 胰腺癌和糖尿病等疾病。TGF-β超家族信号传导 与胰腺分化的各个方面都有密切关系。为 例如，大约50%的胰腺导管癌有突变， 在smad 4中，TGF-β超家族细胞内关键共同介质 发信号。在TGF-β超家族中，TGF-β同种型及其 TGF-β受体II型（TBR-H）特别涉及 在胰腺发育过程中。这项拨款提案的核心假设是 内源性TGF-β亚型信号传导在 诱导外分泌而不是内分泌谱系选择（初级外分泌 谱系选择），并进一步在导管和 腺泡分化（次级外分泌谱系选择）。我们的初步 研究显示TGF-β亚型信号在胰腺癌中的潜在作用， 发展，我们现在希望研究内源性TGF-β亚型的作用， 外分泌初级和次级谱系选择中的信号传导。这些研究 将在正常胚胎、表达一种 显性阴性形式的TBR-II，并在类维生素A诱导的胚胎 胰腺，其显示增强的外分泌分化，无论是腺泡还是 依赖于视色素的导管。方法将首先使用各种 在正常人中抑制内源性TGF-β同种型和/或TBR-II的策略 培养的胚胎胰腺。此外，显性阴性TBR-II转基因 小鼠将允许分析TGF-β同种型信号传导的作用， 特别是在上皮间质相互作用，因为它们适用于我们的 中心假设类维生素A诱导系统将允许我们 关注TGF-β亚型信号在次级外分泌中的作用， 分化（导管与腺泡）。鉴于TGF-β的整体重要性， 胰腺分化中的信号传导，以及 TGF-β信号传导和胰腺分化，从 这些实验应该能增强我们对胰腺发育的理解 以更好地了解胰腺疾病的发病机制。

DESCRIPTION (provided by applicant): The overall goal of our research is to better understand the molecular forces that control pancreatic development and lineage selection. Understanding these forces may allow us to better treat such diseases as pancreatic cancer and diabetes. TGF-beta superfamily signaling has been strongly implicated in all aspects of pancreatic differentiation. For example, approximately 50 percent of pancreatic ductal cancers have mutations in smad4, a critical common mediator of TGF-beta superfamily intracellular signaling. Within the TGF-beta superfamily, the TGF-beta isoforms and their receptor, TGF-beta receptor type II (TBR-H), have been particularly implicated in pancreatic development. The central hypothesis of this grant proposal is that endogenous TGF-beta isoform signaling is specifically important in the induction of exocrine rather than endocrine lineage selection (primary exocrine lineage selection), and further in exocrine differentiation between ductal and acinar differentiation (secondary exocrine lineage selection). Our preliminary studies show a potential role for TGF-beta isoform signaling in pancreatic development, and we now wish to study the role of endogenous TGF-beta isoform signaling in exocrine primary and secondary lineage selection. These studies will be performed in normal embryos, transgenic embryos expressing a dominant-negative form of the TBR-II, and in a retinoid-induced embryonic pancreas, which shows enhanced exocrine differentiation, either acinar or ductal depending on the retinoid. The approach will first be to use various strategies to inhibit endogenous TGF-beta isoforms and/or TBR-II in normal embryonic pancreas in culture. Further, dominant-negative TBR-II transgenic mice will allow analysis of the role of TGF-beta isoform signaling, specifically in epithelial-mesenchymal interactions as they apply to our central hypothesis. The retinoid-induced system will allow us to specifically focus on the role of TGF-beta isoform signaling in secondary exocrine differentiation (ducts vs. acini). Given the overall importance of TGF-beta signaling in pancreatic differentiation, as well as the clinical relevance of TGF-beta signaling and pancreatic differentiation, the information gained from these experiments should enhance our understanding of pancreatic development toward a goal of better understanding the pathogenesis of pancreatic disease.