Program Project,Restoration of Endocrine Pancreas Funct*

计划项目，内分泌胰腺功能的恢复*

• 批准号: 6525303
• 负责人: JOEL F HABENER
• 金额: $ 72.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525303
• 关键词: Rodentias; cell population study; cooperative study; diabetes mellitus; diabetes mellitus therapy; disease /disorder model; genetically modified animals; histogenesis; human tissue; nonhuman therapy evaluation; pancreatic islet function; pancreatic islet transplantation; stem cells

The overall objectives of the studies proposed in this Program Project Application (PPA) are to explore the potential efficacies of using stem/progenitor cells and modified pancreatic islets as cellular therapies to restore endocrine pancreas function and to thereby cure diabetes mellitus. The motivation for this PPA is the fortuitous occurrence of several events: (1) the independent discoveries of pancreatic stem cells by three Harvard investigators, Dr. Susan Bonner-Weir (Joslin), Dr. Joel Habener (Massachusetts General Hospital), and Dr. Richard Mulligan (Childrens' Hospital); (2) the availability from Dr. Douglas Helton (Harvard University) of normalized pancreas cDNA arrays that contain all of the genes express in the pancreas; (3) the development by Dr. Dennis Sgroi (Massachusetts General Hospital) of a means to prepare gene expression profiling probes by Dr. Bennis Sgroi (Massachusetts General Hospital) of a means to prepare gene expression profiling probes from minuscule amounts of tissue obtained by laser capture microdissection; (4) the discovery by Dr. Melissa Thomas (Massachusetts General Hospital) of active hedgehog signaling in the islets of the adult pancreas and (5) the availability from Dr. Gordon Weir (Joslin) of high quality human islets from a preexisting islet transplantation core laboratory. The application proposes three scientific projects and two scientific cores that will work synergistically together to achieve the objectives. Project 1: Pancreas-derived stem/progenitor cells for the regeneration of beta cells (PI: Dr. Bonnor-Weir) has three aims: (1) analysis of distinct populations of duct-derived stem/progenitor cells; (2) gene expression profiling comparisons of human duct-derived versus islet derived stem/progenitor cells during their differentiation; (3) regeneration of beta-cells via transplantation of stem/progenitor cells in animal models of diabetes (rat partial pancreatectomy). Project 2: Modulation of pancreatic islets for transplantation (PI: Dr. Weir) has three aims: (1) evaluation of human islets by expression profiling; (2) determination of the fate of human islets after transplantation; (3) differentiation of transplanted stem/progenitor cells (NIPs, ductal progenitors, SP cells, and others. Project 3: Morphogen signaling during pancreatic islet development (PI: Dr. Thomas) has three aims: (1) mechanisms by which hedgehog signaling regulates expression of homeodomain protein IDX-1; (2) role of hedgehog signaling in the differentiation of pancreas-derived stem/progenitor cells into beta-cells; (3) hedgehog signaling in beta-cell development in vivo. The two scientific cores are: Core B: Islet isolation and transplantation (CD: Dr. Weir) and Core C: Laser capture microdissection and gene expression profiling (Co-CDs: Drs. Sgroi and Melton). All three projects will be heavy users of the two cores. In fact. The cores are the heart of the project, without which the objectives of the project could not be accomplished The two scientific cores are already established and running as components of the Harvard JDRF Islet Transplantation Center. In addition, all participants in this PPA application are members of one of the two NIDDK-funded Diabetes Endocrinology Research Centers (Joslin and MGH-based). An important aspect of this PPA is that the participants will be amongst the first to profile gene expression on cDNA arrays that incorporate all of the genes expressed in the pancreas and allow for determinations of the differences in genes expressed in healthy versus diseased islets and the genes expressed during the differentiation of stem/progenitor5 cells into beta-cells. This PPA proposes the initial studies on the way to providing a cure for diabetes via the approaches for regenerative medicine.

本计划项目申请（PPA）中提出的研究的总体目标是探索使用干/祖细胞和修饰胰岛作为细胞疗法来恢复内分泌胰腺功能并从而治愈糖尿病的潜在功效。本 PPA 的动机是几个事件的偶然发生：(1) 三位哈佛大学研究人员独立发现了胰腺干细胞，他们是 Susan Bonner-Weir 博士（乔斯林）、Joel Habener 博士（马萨诸塞州总医院）和 Dr. Joel Habener 博士（麻省总医院）。理查德·穆里根（儿童医院）； (2) Douglas Helton 博士（哈佛大学）提供标准化胰腺 cDNA 阵列，其中包含胰腺中表达的所有基因； (3)Dennis Sgroi博士(马萨诸塞总医院)开发了一种制备基因表达谱探针的方法 Bennis Sgroi博士(马萨诸塞总医院)开发了一种从通过以下方法获得的微量组织中制备基因表达谱探针的方法激光捕获显微切割； (4) Melissa Thomas 博士（马萨诸塞州总医院）在成人胰腺胰岛中发现了活跃的刺猬信号传导，以及 (5) Gordon Weir 博士（Joslin）通过预先存在的胰岛移植获得了高质量的人类胰岛核心实验室。该申请提出了三个科学项目和两个科学核心，它们将协同工作以实现目标。项目 1：用于再生 β 细胞的胰腺源性干/祖细胞（PI：Bonnor-Weir 博士）有三个目标：（1）分析不同的导管源性干/祖细胞群体； (2) 人导管来源的干细胞/祖细胞与胰岛来源的干/祖细胞在分化过程中的基因表达谱比较； (3) 在糖尿病动物模型中通过干细胞/祖细胞移植实现β细胞的再生（大鼠部分胰腺切除术）。项目2：用于移植的胰岛调节（PI：Weir 博士）有三个目标：（1）通过表达谱评估人类胰岛； (2) 人胰岛移植后命运的测定； (3) 移植干细胞/祖细胞（NIP、导管祖细胞、SP 细胞等）的分化。项目 3：胰岛发育过程中的 Morphogen 信号传导（PI：Thomas 博士）有三个目标：(1) 刺猬信号传导的机制调节同源结构域蛋白 IDX-1 的表达；（2）hedgehog 信号在胰腺干细胞/祖细胞分化为 β 细胞中的作用； β 细胞体内发育的两个科学核心是：核心 B：胰岛分离和移植（CD：Weir 博士）和核心 C：激光捕获显微切割和基因表达谱分析（共同 CD：Sgroi 博士和 Melton 博士）。所有三个项目都将是这两个核心的大量用户。事实上，核心是该项目的核心，没有它，该项目的目标就无法实现。这两个科学核心已经作为哈佛 JDRF 的组成部分建立并运行。此外，本 PPA 申请的所有参与者都是 NIDDK 资助的两个糖尿病内分泌研究中心（位于 Joslin 和 MGH）之一的成员。该 PPA 的一个重要方面是，参与者将成为第一批在 cDNA 阵列上分析基因表达的人之一，该阵列包含胰腺中表达的所有基因，并允许确定健康与患病胰岛中表达的基因的差异以及基因的差异。在干/祖细胞 5 细胞分化为 β 细胞期间表达。该 PPA 提出了通过再生医学方法治愈糖尿病的初步研究。