Regenerating Beta Cells by Lineage Reprogramming

通过谱系重编程再生β细胞

• 批准号: 8316302
• 负责人: DOUGLAS A MELTON
• 金额: $ 67.2万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316302
• 关键词: Adenovirus Vector; Adenoviruses; Adult; Animals; Autoimmune Process; B-Lymphocytes; Beta Cell; Cell Lineage; Cells; Disease; Endoderm Cell; Epigenetic Process; Exocrine pancreas; Foundations; Frequencies; Generations; Genetic; Genetic Models; Genetic Screening; Goals; Hepatocyte; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Intestines; Knowledge; Liver; Methodology; Methods; Molecular; Mouse Strains; Mus; Natural regeneration; Organ; Pancreas; Population; Principal Investigator; Property; RNA; Replacement Therapy; Reporter Genes; Research; Series; System; Technology; Testing; Tissues; Transgenic Mice; Viral Vector; Virus Diseases; base; cell type; chemical genetics; immunogenic; improved; in vivo; insight; islet; mature animal; mouse model; novel; public health relevance; regenerative; small molecule; tool; transcription factor; vector

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.

描述（由申请人提供）：谱系重编程，即成体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，近年来已成为再生因疾病或损伤而损失的细胞的有前途的方法。这种再生方法可能对治疗 1 型糖尿病有价值，因为自身免疫攻击会破坏分泌胰岛素的细胞。该提案的长期目标是制定策略，将内胚层器官的成体细胞重新编程为胰腺β细胞，用于细胞替代疗法。在最近的一项研究中，我们的研究小组表明，通过三种转录因子的组合，可以将成年动物的胰腺外分泌细胞重新编程为分泌胰岛素的β细胞。我们建议扩展这项研究并构建一套新工具来研究重编程机制，并研究几种相关内胚层细胞类型（包括胰腺外分泌细胞、肝细胞和肠细胞）重编程为 ¿ 细胞。 在具体目标 I 中，我们将开发新一代病毒载体，以剖析外分泌细胞体内重编程为 β 细胞的分子和表观遗传机制。在特定目标 II 中，我们将开发诱导型小鼠遗传模型来研究成体内胚层细胞体内重编程为 β 细胞的情况。在特定目标 III 中，我们将使用化学和遗传筛选将肝细胞离体重新编程为 β 细胞。总之，这些研究预计将对 β 细胞重编程机制产生重要的见解，并帮助定义其他细胞类型和重编程方法以在成人中再生 β 细胞。这些工具和知识将为开发针对 1 型糖尿病的新型细胞替代疗法奠定基础。 公共健康相关性：我们提出的研究主要旨在开发新型胰腺β细胞替代疗法，以治疗 1 型糖尿病。具体来说，我们将开发新的研究工具来定义胰腺、肝脏和肠道细胞可以转化为功能性β细胞的细胞类型和条件。