Regenerating Beta Cells by Lineage Reprogramming

描述(申请人提供)：谱系重编程，即成年器官的细胞从一种特殊的细胞类型转化为另一种细胞类型，近年来出现了一种很有前途的方法，可以再生因疾病或损伤而丢失的细胞。这种再生方法可能被证明对1型糖尿病的治疗很有价值，在1型糖尿病中，胰岛素分泌细胞被自身免疫攻击破坏。这项提议的长期目标是设计策略，将内胚层器官的成体细胞重新编程为胰腺细胞，用于细胞替代治疗。在最近的一项研究中，我们的研究小组表明，在成年动物中，胰腺外分泌细胞可以通过三种转录因子的组合重新编程为胰岛素分泌细胞。我们建议扩展这项研究，建立一套新的工具来研究重编程的机制，并研究几种相关的内皮细胞类型，包括胰腺外分泌细胞、肝细胞和肠细胞，重编程为~细胞。 在特定的目标I中，我们将开发新一代病毒载体来剖析体内外分泌细胞重新编程为？细胞的分子和表观遗传学机制。在特定的目的II中，我们将建立可诱导的小鼠遗传模型，以研究成人内皮细胞体内重编程为β-细胞。在特殊目的III中，我们将使用化学和遗传筛选将肝细胞重新编程为体外培养的？-细胞。总之，这些研究有望对β-细胞重新编程的机制产生重要的见解，并有助于确定更多的细胞类型和重新编程方法，以在成人中再生？-细胞。这些工具和知识将为开发治疗1型糖尿病的新型细胞替代疗法奠定基础。 公共卫生相关性：我们建议的研究主要是为了开发新的胰腺细胞替代疗法，以治疗1型糖尿病。具体地说，我们将开发新的研究工具来定义胰腺、肝脏和肠道的细胞类型和条件，从而将细胞转化为功能细胞。

DESCRIPTION (provided by applicant): Lineage reprogramming, whereby cells of adult organs are converted from one specialized cell type into another, has emerged in recent years as a promising approach to regenerate cells lost due to disease or injury. This regenerative approach could prove valuable for the treatment of Type 1 diabetes where insulin secreting ¿-cells are destroyed by autoimmune attacks. The long-term goal of this proposal is to devise strategies to reprogram adult cells of endodermal organs into pancreatic ?-cells for cell replacement therapies. In a recent study, our research groups showed that pancreatic exocrine cells can be reprogrammed into insulin secreting ?-cells in adult animals by a combination of three transcription factors. We propose to expand on this study and build a set of new tools to investigate the mechanisms of reprogramming and study the reprogramming of several related endodermal cell types, including pancreatic exocrine cells, liver cells and intestine cells, into ¿-cells. In Specific Aim I, we will develop a new generation of viral vectors to dissect the molecular and epigenetic mechanisms of in vivo reprogramming of exocrine cells into ?-cells. In Specific Aim II, we will develop inducible mouse genetic models to investigate the in vivo reprogramming of adult endodermal cells to ?-cells. In Specific Aim III, we will use chemical and genetic screens to reprogram hepatocytes to ?-cells ex vivo. Together, these studies are expected to yield important insights into the mechanism of ?-cell reprogramming and help define additional cell types and reprogramming methodologies to regenerate ?-cells in the adult. Such tools and knowledge will form the foundation for developing novel cell replacement therapies for Type 1 diabetes. PUBLIC HEALTH RELEVANCE: Our proposed studies are broadly aimed at developing novel cell replacement therapies for pancreatic ?-cells in order to treat type 1 diabetes. Specifically, we will develop new research tools to define the cell types and conditions whereby cells of pancreas, liver, and intestine can be converted into functional ?-cells.