Activin vs BMP Signaling in Pancreatic Lineage Selection

描述（由申请人提供）：我们研究的总体目标是更好地了解正常的体内胰腺分化机制，以便我们以后可以将这些知识应用于工程细胞的创造，用于胰岛素依赖性糖尿病的替代治疗和治愈。我们的研究重点是细胞外信号机制，因为这样的途径可以更容易地应用于目前可用的干细胞群体，干细胞实验室的初步数据已经显示出一些有希望的早期成功，这些干细胞群体有能力被操纵成胰岛素阳性表型。我们的实验室在研究胚胎胰腺发育，特别是间充质细胞对胰腺上皮分化和谱系选择的影响方面有着丰富的经验。在这项拨款申请中，我们希望研究激活素和BMP信号传导在胰腺谱系选择中的基本作用机制，以及这两种信号传导途径之间的潜在相互作用。我们的中心假设是，这两种途径对于控制内分泌（激活素诱导）或外分泌/腺泡（bmp诱导）分化至关重要，这两种途径之间的竞争决定了早期胚胎胰腺的净外分泌与内分泌室分化。在具体的目标1中，我们将更好地定义激活素信号分子和下游smad的途径和作用，然后通过简单的smad阻断研究，测试激活素途径在胰上皮前体细胞工程胰腺内分泌细胞中的潜在效用。在特定目标2中，将研究BMP信号通路及其抑制剂的特定方面，以研究其在胰腺发育中的潜在促外分泌和抗内分泌作用。最后，由于激活素和BMP信号通路相互影响是众所周知的，在特定的目的3中，我们将研究这两种信号通路之间相互作用的潜在机制，这可能有助于发育中的胰腺的整体谱系选择。总的来说，通过这些研究，我们希望更好地了解特定的细胞外信号通路，这些信号通路可能用于操纵干细胞或胰腺祖细胞成为胰岛素阳性β细胞，以治疗糖尿病。

DESCRIPTION (provided by applicant): The overall goal of our research is to better understand normal in vivo mechanisms of pancreatic differentiation so that we may later apply this knowledge to the creation of engineered cells for replacement therapy and cure of insulin dependent diabetes mellitus. We have focused our studies on extracellular signaling mechanisms, since such pathways could more easily be applied to the stem cell populations currently available, and preliminary data in stem cell laboratories have shown some promising early success with the ability of these stem cell populations to be manipulated toward an insulin-positive phenotype. Our laboratory has extensive experience in the study of embryonic pancreatic development and, in particular, mesenchymal influences on pancreatic epithelial differentiation and lineage selection. In this grant proposal we wish to study the basic mechanisms of action of activin and BMP signaling in pancreatic lineage selection, as well as potential interplay between these two signaling pathways. Our central hypothesis is that these two pathways are critical to controlling endocrine (activin-induced) or exocrine/acinar (BMP-induced) differentiation, and that competition between these two pathways determines the net exocrine versus endocrine compartment differentiation in the early embryonic pancreas. In specific aim 1, we will better define the pathways and roles of activin signaling molecules and downstream smads, and then test the potential utility of activin pathways in engineering pancreatic endocrine cells from pancreatic epithelial precursor cells through simple smad-blocking studies. In specific aim 2, an analysis of specific aspects of the BMP signaling pathway and its inhibitors will be studied for a potential pro-exocrine and anti-endocrine role in pancreatic development. Lastly, since activin and BMP signaling are well known to affect one another, in specific aim 3 we will study potential mechanisms for interplay between these two signaling pathways that may contribute to overall lineage selection in the developing pancreas. Overall, through these proposed studies, we hope to better understand the specific extracellular signaling pathways that may be usable for the manipulation of stem cells or pancreatic progenitor cells into becoming insulin-positive beta-cells for the treatment of diabetes mellitus.