Derivation of human pluripotent stem cells using small molecules

使用小分子衍生人类多能干细胞

• 批准号: 7822514
• 负责人: YANHONG SHI
• 金额: $ 100万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822514
• 关键词: Address; Alzheimer' s Disease; Area; Brain Injuries; Cell Line; Cell Lineage; Cells; Cellular Morphology; Chemicals; Derivation procedure; Development; Developmental Biology; Disease; Embryo; Epigenetic Process; Fibroblasts; Gene Expression; Gene Transfer; Generations; Genes; Genetic; Goals; Human; Human Cloning; Human Engineering; Immature Teratoma; Lead; Libraries; Luciferases; Malignant Neoplasms; Methods; Morphology; Mus; Neurodegenerative Disorders; Parkinson Disease; Patients; Plasmids; Pluripotent Stem Cells; Problem Solving; Process; Puromycin; Regenerative Medicine; Regulation; Replacement Therapy; Reporter Genes; Research; Resistance; Risk; Screening procedure; Somatic Cell; Stem cells; Technology; Therapeutic; Transfection; Transgenes; Transgenic Organisms; Viral; Virus; base; drug discovery; egg; embryonic stem cell; genetic manipulation; high throughput screening; human embryonic stem cell; human stem cells; induced pluripotent stem cell; nerve stem cell; nervous system disorder; pluripotency; promoter; public health relevance; retroviral transduction; self-renewal; small molecule; stem cell differentiation; stem cell therapy; tool; transcription factor; transgene expression; tumorigenesis

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (14: Stem Cells) and specific Challenge Topic (14-NS-101: Reverse Engineering Human Neurological Disease). Viral or plasmid introduction of a transcription factor quartet is proven a powerful strategy to trigger reprogramming somatic cells into induced pluripotent stem (iPS) cells without the need of embryos or eggs. However, genetic manipulation using transgenes represents a serious hurdle to the use of these iPS cells for therapeutic application. While reactivation of trangenes could lead to tumorigenesis, leaky expression of transgenes may inhibit iPS cell differentiation, increasing the risk of immature teratoma formation. One way to solve this problem is to identify small molecules that induce endogenous pluripotent regulators without gene transfer. Furthermore, generation of iPS cells using existing technology by viral transduction or plasmid transfection of the reprogramming factors is a process with very low efficiency. The main goal of this research is to derive transgene-free human iPS cells using small molecules and to identify compounds that enhance reprogramming efficiency. This study will lead to the development of new methods for the derivation ofpluripotent human stem cell lines with high efficiency and open a new avenue to generate patient- and disease-specific pluripotent stem cells. These chemically derived iPS cells will become valuable tools for developmental biology, drug discovery, and regenerative medicine. PUBLIC HEALTH RELEVANCE: Chemical derivation of human iPS cells in virus-free and transgene-free means will open a new avenue to generate patient- and disease-specific pluripotent stem cells with high efficiency. These genetically unmodified iPS cells will be applicable in stem cell-based cell replacement therapies for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and brain injuries.

描述（由申请人提供）：本申请涉及广泛的挑战领域（14：干细胞）和特定的挑战主题（14-NS-101：逆向工程人类神经系统疾病）。转录因子四联体的病毒或质粒引入被证明是一种强有力的策略，可以在不需要胚胎或卵子的情况下触发体细胞重编程为诱导多能干细胞（iPS）。然而，使用转基因的遗传操作代表了将这些iPS细胞用于治疗应用的严重障碍。虽然转基因的再激活可能导致肿瘤发生，但转基因的泄漏表达可能抑制iPS细胞分化，增加未成熟畸胎瘤形成的风险。解决这一问题的一种方法是鉴定诱导内源性多能调节因子而无需基因转移的小分子。此外，使用现有技术通过病毒转导或质粒转染重编程因子来产生iPS细胞是效率非常低的方法。这项研究的主要目标是使用小分子衍生出无转基因的人类iPS细胞，并确定提高重编程效率的化合物。本研究将为高效诱导多能干细胞系的建立提供新的方法，为产生患者和疾病特异性多能干细胞开辟新的途径.这些化学衍生的iPS细胞将成为发育生物学、药物发现和再生医学的宝贵工具。 公共卫生相关性：以无病毒和无转基因的方式化学衍生人iPS细胞将为高效产生患者和疾病特异性多能干细胞开辟新途径。这些基因未修饰的iPS细胞将可用于基于干细胞的细胞替代疗法，用于治疗神经退行性疾病，如阿尔茨海默病和帕金森病以及脑损伤。