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胰腺分化的正常体内机制，以便我们以后可以将这些知识应用于创建用于替代疗法和治愈胰岛素依赖性糖尿病的工程细胞。我们把我们的研究集中在细胞外信号传导机制，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，在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与这些干细胞群体的能力，以操纵胰岛素阳性表型。我们实验室在胚胎胰腺发育的研究方面有着丰富的经验，特别是间充质对胰腺上皮分化和谱系选择的影响。 在这项资助计划中，我们希望研究激活素和BMP信号在胰腺谱系选择中的基本作用机制，以及这两种信号通路之间的潜在相互作用。我们的中心假设是，这两种途径是至关重要的控制内分泌（激活素诱导）或外分泌/腺泡（BMP诱导）分化，这两种途径之间的竞争决定了净外分泌与内分泌区室分化的早期胚胎胰腺。在具体目标1中，我们将更好地定义激活素信号分子和下游smads的通路和作用，然后通过简单的smad阻断研究来测试激活素通路在从胰腺上皮前体细胞工程化胰腺内分泌细胞中的潜在效用。在具体目标2中，将研究BMP信号传导途径及其抑制剂的特定方面的分析，以确定其在胰腺发育中的潜在促外分泌和抗内分泌作用。最后，由于众所周知激活素和BMP信号传导相互影响，在具体目标3中，我们将研究这两种信号传导途径之间相互作用的潜在机制，这可能有助于发育中胰腺的整体谱系选择。 总的来说，通过这些拟议的研究，我们希望更好地了解特定的细胞外信号通路，这些信号通路可用于操纵干细胞或胰腺祖细胞成为胰岛素阳性β细胞，用于治疗糖尿病。

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.