Characterizing the Role of Pancreatic Progenitors in Regeneration

描述胰腺祖细胞在再生中的作用

• 批准号: 9137682
• 负责人: Michael J Parsons
• 金额: $ 35.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137682
• 关键词: Ablation; Adult; Animal Model; Autoimmunity; Beta Cell; Biological Models; Biology; Cell Differentiation process; Cells; Cellular biology; Chemicals; Complex; Development; Diabetes Mellitus; Ductal; Ductal Epithelial Cell; Endocrine; Environment; Experimental Models; FDA approved; Fishes; Funding; Future; Genes; Genetic; Goals; Hand; Homeostasis; Human; Image; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Larva; Learning; Maps; Methods; Modeling; Molecular; Morphology; Natural regeneration; Operative Surgical Procedures; Organ; Organism; Pancreas; Pancreatectomy; Pancreatitis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Population; Preclinical Drug Evaluation; Process; Property; Recovery; Regenerative response; Regulation; Role; Signal Transduction; Speed; Staging; Structure of beta Cell of islet; System; Techniques; Technology; Testing; Therapeutic; Tissues; Transgenic Organisms; Work; Zebrafish; arm; cell injury; cell type; design; experience; human disease; islet; molecular marker; notch protein; novel; pancreas development; progenitor; recombinase-mediated cassette exchange; regenerative; therapeutic target; tool; transcriptome; zebrafish development; Ablation; Adult; Animal Model; Autoimmunity; Beta Cell; Biological Models; Biology; Cell Differentiation process; Cells; Cellular biology; Chemicals; Complex; Development; Diabetes Mellitus; Ductal; Ductal Epithelial Cell; Endocrine; Environment; Experimental Models; FDA approved; Fishes; Funding; Future; Genes; Genetic; Goals; Hand; Homeostasis; Human; Image; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Larva; Learning; Maps; Methods; Modeling; Molecular; Morphology; Natural regeneration; Operative Surgical Procedures; Organ; Organism; Pancreas; Pancreatectomy; Pancreatitis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Population; Preclinical Drug Evaluation; Process; Property; Recovery; Regenerative response; Regulation; Role; Signal Transduction; Speed; Staging; Structure of beta Cell of islet; System; Techniques; Technology; Testing; Therapeutic; Tissues; Transgenic Organisms; Work; Zebrafish; arm; cell injury; cell type; design; experience; human disease; islet; molecular marker; notch protein; novel; pancreas development; progenitor; recombinase-mediated cassette exchange; regenerative; therapeutic target; tool; transcriptome; zebrafish development

DESCRIPTION (provided by applicant): Characterizing the role of pancreatic progenitors in regeneration. Our goals are focused on identifying pathways used to generate new beta-cells either during development or regeneration. It is hoped that this approach will identify targets tha can be exploited in the treatment of diabetes. As there is a high degree of conservation in the molecular mechanisms that control vertebrate pancreas development and function, we have turned to the zebrafish as an alternative model system to study beta-cell biology and regeneration. The zebrafish has a remarkable capacity for regenerating tissues following organ damage and we have shown that this ability extends to the insulin producing beta-cells of the pancreas. We reason that it will be easier and faster to study mechanisms involved in tissue recovery in an organism that can readily regenerate. From work done in other systems, it is apparent that different methods of tissue injury can promote different regenerative responses. The most efficient way to learn about the cells and signals involved in regeneration will be to utilize different experimental models of pancreas injury. To these ends our lab has developed: i) An efficient transgenic method to specifically ablate the beta-cells while being able to simultaneously image the remaining islets; ii) Chemically induced pancreatitis destroying the acinar tissue; iii) A surgical procedure to remove a large portion of the pancreas (partial pancreatectomy). In order to ascertain the cells involved in regeneration, we developed the tools and methods to perform long-range lineage tracing in the zebrafish. With this technique, we identified the pancreatic progenitors in the larvae that give rise to endocrine and centroacinar cells of the adult fish. With this technology in hand and the experience gained, we can now fate map different pancreatic cell types and ascertain their role in facultative regeneration following tissue damage from any of our injury models. Many aspects of regeneration recapitulate molecular pathways and mechanisms used during development. For instance, we showed that Notch-signaling was important in regulating beta-cell formation during development and we recently demonstrated that Notch-signaling is dramatically up-regulated following adult pancreas injury. To find more pathways, we carried out a chemical screen for drugs that induce the formation of precocious islets in larval fish. This work led to the identification of several novel pathways involved in beta-cell differentiation. With pharmaceutical and newly developed genetic methods in hand, we can manipulate all these pathways mentioned and study their effects on both pancreas development and regeneration. This work is aimed at ascertaining if these pathways can be manipulated to induce adult beta-cell neogenesis, and provide the platform for future studies in mammalian models.

描述（由申请人提供）：表征胰腺祖细胞在再生中的作用。我们的目标旨在确定用于在开发或再生过程中生成新的β细胞的途径。希望这种方法能够确定可以在糖尿病治疗中利用THA的目标。由于控制脊椎动物胰腺发育和功能的分子机制中有高度的保护，因此我们转向斑马鱼作为研究β细胞生物学和再生的替代模型系统。斑马鱼在器官损伤后具有出色的再生组织能力，我们已经表明，这种能力扩展到产生胰腺β细胞的胰岛素。我们认为，研究可以容易再生的有机体中涉及组织恢复的机制会更容易，更快。从其他系统中完成的工作，很明显，组织损伤的不同方法可以促进不同的再生反应。了解再生的细胞和信号的最有效方法是利用胰腺损伤的不同实验模型。为此，我们的实验室已经开发了：i）一种有效的转基因方法，可以特异性地消灭β细胞，同时能够同时对剩余的胰岛进行图像； ii）化学诱导的胰腺炎破坏了腺泡组织； iii）一种外科手术，以去除大部分胰腺（部分胰腺切除术）。为了确定与再生有关的细胞，我们开发了在斑马鱼中执行远程谱系跟踪的工具和方法。通过这种技术，我们确定了幼虫中的胰腺祖细胞，从而导致成年鱼的内分泌和腹类细胞。借助这项技术并获得了这种经验，我们现在可以命运不同的胰腺细胞类型，并确定它们在我们任何损伤模型的组织损害之后在辅助再生中的作用。再生的许多方面概括了开发过程中使用的分子途径和机制。例如，我们表明，在开发过程中调节β细胞的形成非常重要，我们最近证明，成年胰腺损伤后，凹口信号显着上调。为了找到更多的途径，我们为诱导幼虫鱼中早熟的胰岛形成的药物进行了化学筛选。这项工作导致了几本小说的识别 与β细胞分化有关的途径。借助药物和新开发的遗传学方法，我们可以操纵所有提到的途径，并研究它们对胰腺发育和再生的影响。这项工作旨在确定是否可以操纵这些途径来诱导成人β细胞新生成，并为哺乳动物模型中的未来研究提供平台。