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: 8842977
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842977
• 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; Gene Expression Profile; 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; regenerative; therapeutic target; tool; 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）：描述胰腺祖细胞在再生中的作用。我们的目标集中于确定在发育或再生过程中用于生成新 β 细胞的途径。希望这种方法能够确定可用于治疗糖尿病的目标。由于控制脊椎动物胰腺发育和功能的分子机制具有高度保守性，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非凡的组织再生能力，我们已经证明这种能力延伸到了胰腺中产生胰岛素的β细胞。我们认为，研究易于再生的生物体中参与组织恢复的机制将会更加容易和快捷。从其他系统所做的工作来看，显然不同的组织损伤方法可以促进不同的再生反应。了解参与再生的细胞和信号的最有效方法是利用不同的胰腺损伤实验模型。为此，我们的实验室开发了： i) 一种有效的转基因方法，专门消融 β 细胞，同时能够对剩余的胰岛进行成像； ii) 化学诱发的胰腺炎破坏腺泡组织； iii) 切除大部分胰腺的外科手术（部分胰腺切除术）。为了确定参与再生的细胞，我们开发了在斑马鱼中进行远程谱系追踪的工具和方法。通过这项技术，我们鉴定了幼鱼中产生成鱼内分泌细胞和腺泡中心细胞的胰腺祖细胞。有了这项技术和所获得的经验，我们现在可以绘制不同胰腺细胞类型的命运图谱，并确定它们在我们的任何损伤模型造成的组织损伤后的兼性再生中的作用。再生的许多方面概括了发育过程中使用的分子途径和机制。例如，我们证明了Notch信号传导对于调节发育过程中β细胞的形成很重要，并且我们最近证明了Notch信号传导在成人胰腺损伤后显着上调。为了找到更多途径，我们对诱导幼鱼早熟胰岛形成的药物进行了化学筛选。这项工作导致鉴定了一些新颖的 参与β细胞分化的途径。借助药物和新开发的遗传方法，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体β细胞新生，并为未来在哺乳动物模型中的研究提供平台。