Pancreatic Islet Design & Engineering (SysCODE 3 of 10)

内分泌胰腺既是发育生物学基本问题的基础， 糖尿病是影响全世界数百万人的疾病的目标。详细的基因 对胰腺内分泌发育的分子理解将是至关重要的， 体内胰岛细胞命运和数量。我们对胰腺发育的新认识是， 通过与周围间充质的相互作用，最初未形成图案的胰腺上皮被 依次细分为外分泌和内分泌区室，随后分化， 后者包含|3eta细胞产生胰岛素。决定胰岛细胞特化的因素包括 许多基因的身份现在已经知道了。事实上，现在可以将这些基因排列成第一个 从基因作用、表达和功能相互依赖性的顺序来看，有序遗传调控网络， 等级关系。因此，这项拨款提出了一个问题：我们是否已经知道 足够的，我们能充分增加知识，开始使用这些信息， 体外制造胰岛和胰岛细胞 为了实现这一宏伟目标，我们将采取三个具体目标， SysCODE的多个组件。在目标1中，我们将为基因组中的关键早期状态生成完整的基因列表。 内分泌胰腺发育该领域的初步努力已经完成（Gu等人， Development 131，165-79，2004）。我们现在将用来自其他国家的数据来补充这一信息。 发育阶段、选定的突变状态和第一代蛋白质组学分析。在目标2中， 与SysCODE计算团队合作，我们将开发方法来排序这些基因， 选择的蛋白质进入一个明确的基因调控网络（CRN）的格式，这是有用的生物学家 和组织工程师最后，在目标3中，我们将与SysCODE组织工程团队合作， 实现一个基于干细胞的胰岛发育工程模型，我们将使用GRNs 在目的2中生成以优化胰腺内分泌命运规范。在拨款的最后几年，我们将 将工程化胰岛移植到糖尿病小鼠体内并评估其生理功能。总的来说，这些 与SysCODE的其余部分一起，将建立一个再生的转换范式， 药

The endocrine pancreas is both the substrate for fundamental questions in developmental biology as well as the target of the disease diabetes mellitus, which affects millions of individuals worldwide. A detailed genetic and molecular understanding of pancreatic endocrine development will be essential if we are to manipulate islet cell fate and numbers in vivo. Our emerging understanding of pancreatic development is one in which, through interactions with surrounding mesenchyme, the initially unpatterned pancreatic epithelium is successively sub-divided into exocrine and endocrine compartments which subsequently differentiate, the latter containing the |3eta cells that produce insulin. Among the factors that dictate islet cell specification are many genes whose identities are now known. In fact, it is now possible to order these genes into a first order genetic regulatory network in terms of order of gene action, expression and functional interdependencies, and hierarchical relationships. This grant therefore poses the question: Do we already know enough, and can we sufficiently augment that knowledge, to begin to use this information to systematically engineer islets and islet cells in vitro? To accomplish this ambitious goal, we will undertake three Specific Aims that are highly integrated with multiple components of SysCODE. In Aim 1, we will generate complete gene lists for key early states in the developing endocrine pancreas. An initial effort in this area has already been accomplished (Gu et al., Development 131, 165-79, 2004). We will now augment this information with data from additional developmental stages, selected mutant states and first-generation proteomic analyses. In Aim 2, in conjunction with the SysCODE Computational Team, we will develop methodology to order these genes and selected proteins into a definitive gene regulatory network (CRN) in a format that is useful to both biologists and tissue engineers. Lastly, in Aim 3 we will collaborate with the SysCODE Tissue Engineering Team to implement a stem cell based, engineered model of pancreatic islet development and we will use the GRNs generated in Aim 2 to optimize pancreatic endocrine fate specification. In the out years of the grant, we will transplant the engineered islets into diabetic mice and assess their physiological function. Collectively, these efforts, in conjunction with the rest of SysCODE, will establish a transforming paradigm for regenerative medicine.