Regenerating Beta Cells by Lineage Reprogramming

描述（由申请人提供）：谱系重编程，即成年器官的细胞从一种特化细胞类型转化为另一种细胞类型，近年来作为一种有前途的方法出现，用于再生因疾病或损伤而丢失的细胞。这种再生方法对于治疗胰岛素分泌细胞被自身免疫攻击破坏的1型糖尿病很有价值。本提案的长期目标是设计策略，将内胚层器官的成年细胞重编程为胰腺？-细胞替代疗法的细胞。在最近的一项研究中，我们的研究小组表明，胰腺外分泌细胞可以被重新编程为分泌胰岛素？-通过三种转录因子的组合在成年动物的细胞中。我们建议在此基础上，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胚层细胞类型，包括胰腺外分泌细胞、肝细胞和肠细胞，重编程为¿-细胞。

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.