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恢复内分泌胰腺功能并从而治愈糖尿病的潜在疗效。这个PPA的动机是几个事件的偶然发生：（1）三个哈佛研究者，苏珊·邦纳-威尔博士（乔斯林），乔尔·哈伯纳博士（马萨诸塞州总医院）和理查德·穆里根博士（儿童医院）;（2）道格拉斯赫尔顿博士的可用性（哈佛大学）的标准化胰腺cDNA阵列，其包含胰腺中表达的所有基因;（3）Dennis Sgroi博士的发展（马萨诸塞州综合医院）的方法来制备基因表达谱探针（马萨诸塞州总医院）从激光捕获显微切割获得的微量组织中制备基因表达谱探针的方法;（4）Melissa托马斯博士（马萨诸塞州综合医院）发现了成年胰腺胰岛中的活性hedgehog信号传导，以及（5）Gordon Weir博士（Joslin）从先前存在的胰岛移植核心实验室获得了高质量的人胰岛。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。项目一：胰腺源性干/祖细胞用于β细胞再生（PI：Bonnor-Weir博士）有三个目的：（1）分析不同的导管衍生干/祖细胞群体;（2）比较人导管衍生干/祖细胞与胰岛衍生干/祖细胞在分化过程中的基因表达谱;（3）通过在糖尿病动物模型（大鼠部分胰腺切除术）中移植干/祖细胞再生β细胞。项目二：用于移植的胰岛的调节（PI：Dr. Weir）具有三个目的：（1）通过表达谱评估人胰岛;（2）确定移植后人胰岛的命运;（3）移植的干/祖细胞（NIP、导管祖细胞、SP细胞等）的分化。项目三：胰岛发育过程中的形态发生素信号传导（PI：Dr.托马斯）具有三个目的：（1）hedgehog信号传导调节同源域蛋白IDX-1表达的机制;（2）hedgehog信号传导在胰腺源性干/祖细胞分化成β细胞中的作用;（3）体内β细胞发育中的hedgehog信号传导。这两个科学核心是：核心B：胰岛分离和移植（CD：Dr. Weir）和核心C：激光捕获显微切割和基因表达谱（Co-CD：Dr. Sgroi和Melton）。这三个项目都将是这两个核心的重度用户。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建立并作为哈佛JDRF胰岛移植中心的组成部分运行。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（乔斯林和MGH）之一的成员。该PPA的一个重要方面是，参与者将是第一批在cDNA阵列上分析基因表达的人，该cDNA阵列包含胰腺中表达的所有基因，并允许确定健康胰岛与患病胰岛中表达的基因以及干/祖细胞分化为β细胞期间表达的基因的差异。该PPA提出了通过再生医学方法治疗糖尿病的初步研究。