Pancreatic Islet Design & Engineering (SysCODE 3 of 10)

胰岛设计

基本信息

批准号：
8106142
负责人：
DOUGLAS A MELTON
金额：
$ 55.26万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-06-30
项目状态：
已结题

项目摘要

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.

内分泌胰腺既是发育生物学基本问题的基础，也是糖尿病是影响全世界数百万人的疾病的目标。详细的遗传如果我们要操纵胰腺内分泌发育，那么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的命运和数量。我们对胰腺发育的新认识是：通过与周围间质的相互作用，最初无图案的胰腺上皮依次细分为外分泌区和内分泌区，随后又分化，后者含有产生胰岛素的|3eta细胞。决定胰岛细胞规格的因素包括许多基因的身份现在已为人所知。事实上，现在可以将这些基因排序为第一个根据基因作用、表达和功能相互依赖性的顺序排列遗传调控网络，和层级关系。因此，这笔赠款提出了一个问题：我们是否已经知道足够了，我们能否充分增强这些知识，开始系统地使用这些信息体外改造胰岛和胰岛细胞？为了实现这一雄心勃勃的目标，我们将实现三个与以下目标高度结合的具体目标： SysCODE 的多个组件。在目标 1 中，我们将为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，发展 131, 165-79, 2004)。我们现在将使用来自其他数据的数据来扩充此信息发育阶段、选定的突变状态和第一代蛋白质组分析。在目标 2 中，我们将与 SysCODE 计算团队一起开发对这些基因进行排序的方法选择的蛋白质以对生物学家都有用的格式进入明确的基因调控网络 (CRN) 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施基于干细胞的胰岛发育工程模型，我们将使用 GRN 在目标 2 中生成以优化胰腺内分泌命运规范。在赠款的最后几年，我们将将工程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 的其余部分一起努力，将为再生建立一个转变范式药品。