Program Project,Restoration of Endocrine Pancreas Funct*

计划项目，内分泌胰腺功能的恢复*

• 批准号: 6653849
• 负责人: JOEL F HABENER
• 金额: $ 75.04万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653849
• 关键词: clinical research; cooperative study; diabetes mellitus; diabetes mellitus therapy; pancreatic islet function; pancreatic islet transplantation

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.

该计划项目应用（PPA）提出的研究的总体目标是探讨使用干/祖细胞和修饰的胰岛作为细胞疗法的潜在功效，以恢复内分泌胰腺功能，从而治愈糖尿病。该PPA的动机是几个事件的偶然发生：（1）三名哈佛大学研究人员Susan Bonner-Weir（Joslin），Joel Habener（马萨诸塞州总医院）和Richard Mulligan（Childrens'Hospits）的胰腺干细胞独立发现； （2）从胰腺中包含所有表达的基因的标准化胰腺dna阵列的道格拉斯·赫尔顿（Douglas Helton）博士的可用性； （3）丹尼斯·斯格罗伊（Dennis Sgroi）博士（马萨诸塞州综合医院）的开发方法是准备基因表达分析探针Bennis Sgroi博士（马萨诸塞州综合医院）的一种手段，该手段是通过激光捕获微分辨率获得的微量组织量的基因表达探针来制备基因表达探针。 （4）梅利莎·托马斯（Melissa Thomas）（马萨诸塞州综合医院）的发现，成人胰腺胰岛中的主动刺猬信号传导，以及（5）（5）高品质的人类胰岛的戈登·韦尔（Gordon Weir）博士的可用性，该胰岛从预科岛及其岛屿上的核心移植核心移植实验室的高品质人类胰岛。该申请提出了三个科学项目和两个科学核心，它们将协同合作以实现目标。项目1：用于β细胞再生的胰腺源性干/祖细胞（PI：Bonnor-Weir博士）具有三个目的：（1）分析导管衍生的茎/祖细胞的不同种群； （2）在分化过程中，人类导管衍生的茎/祖细胞的基因表达分析比较； （3）通过在糖尿病动物模型（大鼠部分胰腺切除术）中移植茎/祖细胞的β细胞再生。项目2：移植胰岛的调节（PI：Weir博士）具有三个目的：（1）通过表达谱分析评估人类胰岛； （2）在移植后确定人类胰岛的命运； （3）移植的茎/祖细胞（NIP，导管祖细胞，SP细胞和其他）的分化。项目3：胰岛发育过程中的形态学信号（PI：Thomas博士）具有三个目的：（1）刺激性信号调节hedgeHog信号的机制，可调节源代码蛋白质IDX-1;（2）prandies dydex-1;（茎/祖细胞在体内的β细胞发育中的刺猬信号是：核心核心：核心的孤立和移植。如果没有该项目，该项目就无法实现，这两个科学核心已经建立，并作为哈佛JDRF ISLET移植中心的组成部分运行。该PPA的一个重要方面是，参与者将成为第一个在胰腺中融合了所有表达的cDNA阵列中基因表达的人之一，并允许确定在健康疾病胰岛中表达的基因的差异，以及在STEM/procenitor5细胞分化中表达的基因中表达的基因。该PPA提出了有关通过再生医学方法提供糖尿病治疗方法的最初研究。