Regenerating Beta Cells by Lineage Reprogramming

通过谱系重编程再生β细胞

• 批准号: 8522193
• 负责人: DOUGLAS A MELTON
• 金额: $ 69.12万
• 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/8522193
• 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，即成年器官的细胞从一种专门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丢失的细胞的有希望的方法。这种再生方法可能被证明对治疗1型糖尿病有价值，在这种糖尿病中，胰岛素分泌细胞被自身免疫攻击破坏。这项提案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？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，胰腺外分泌细胞可以重新编程为胰岛素分泌细胞。在成年动物的细胞中通过三种转录因子的组合。我们建议扩展这项研究，并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。 在特定目标I中，我们将开发新一代病毒载体，以剖析外分泌细胞在体内重编程为？细胞在特定目标II中，我们将开发诱导型小鼠遗传模型，以研究成体内胚层细胞在体内重编程为？细胞在特定目标III中，我们将使用化学和遗传筛选将肝细胞重编程为？离体细胞。总之，这些研究预计将产生重要的见解？细胞重编程和帮助定义额外的细胞类型和重编程方法再生？成人的细胞。这些工具和知识将成为开发1型糖尿病新型细胞替代疗法的基础。 公共卫生相关性：我们提出的研究广泛旨在开发用于胰腺癌的新型细胞替代疗法。1型糖尿病的治疗方法具体而言，我们将开发新的研究工具，以确定胰腺，肝脏和肠道细胞可以转化为功能性细胞的细胞类型和条件。细胞