Reprogramming using small molecules

使用小分子重编程

• 批准号: 8829869
• 负责人: KEVIN C EGGAN
• 金额: $ 31.55万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829869
• 关键词: Adult; Biochemical Genetics; Biology; Bupivacaine; Cell Line; Cells; Chemicals; Clinical; Disease; Disease model; Doctor of Philosophy; Drug Formulations; Future; Genes; Genome; Goals; Human; Methods; Molecular; Pathway interactions; Patients; Process; Production; Prostaglandins; Somatic Cell; Stem cells; Testing; Transgenic Organisms; Uncertainty; Work; c-Myc Staining Method; cell type; drug discovery; genetic approach; genetic manipulation; human disease; induced pluripotent stem cell; interest; professor; regenerative; ropivacaine; screening; small molecule; transcription factor; transplantation medicine

DESCRIPTION (provided by applicant): The combined activity of four transcription factors (Oct4, Sox2, cMyc and Klf4) can reprogram adult cells into induced pluripotent stem (iPS) cells. These reprogrammed cells should provide a limitless supply of genetically tailored cell types for transplantation medicine, drug discovery and the study of human disease. Unfortunately, the methods used to deliver reprogramming factors have either raised concerns regarding the future utility of the resulting stem cells, or may not be compatible with industrial scale production of clinically compatible stem cell lines. Here, we propose to determine the mechanisms of action of small molecules that we have shown can facilitate the reprogramming process by either increasing its efficiency or by allowing the omission of one or more reprogramming factors. Our final goal is to move towards the identification of a chemical formulation that can alone reprogram adult cells to a pluripotent state. These reprogrammed cells would be free of genetic manipulation and would be the optimal pluripotent cells for biomedical applications. Specifically the aims are: aim 1) To determine the mechanisms by which newly identified small reprogramming molecules act to replace Klf4 in the reprogramming process; aim 2) To determine the mechanisms by which newly identified small reprogramming molecules that can replace Oct4 act in the reprogramming process; aim 3) To determine whether the reprogramming molecules that we have identified can act synergistically to replace multiple reprogramming transcription factors, thus moving us closer to a completely chemical method for reprogramming.

描述（由申请人提供）：四种转录因子（Oct4, Sox2， cMyc和Klf4）的联合活性可以将成人细胞重编程为诱导多能干细胞（iPS）细胞。这些重新编程的细胞将为移植医学、药物发现和人类疾病研究提供无限的基因定制细胞类型。不幸的是，用于传递重编程因子的方法要么引起了对所产生的干细胞未来效用的担忧，要么可能与临床兼容的干细胞系的工业规模生产不兼容。在这里，我们建议确定小分子的作用机制，我们已经表明，可以通过提高其效率或允许遗漏一个或多个重编程因子来促进重编程过程。我们的最终目标是确定一种化学制剂，可以单独将成年细胞重新编程为多能状态。这些重新编程的细胞将不受基因操纵，将成为生物医学应用的最佳多能细胞。具体目标是：目的1)确定新发现的小重编程分子在重编程过程中取代Klf4的机制；目的2)确定新发现的可取代Oct4的小重编程分子在重编程过程中的作用机制；目的3)确定我们已经确定的重编程分子是否可以协同作用来取代多个重编程转录因子，从而使我们更接近于完全化学的重编程方法。