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Generation of Induced Pluripotent Stem Cells with Novel Small Molecule Regulator

使用新型小分子调节剂生成诱导多能干细胞

基本信息

批准号：
7836639
负责人：
Xiaodong Cheng
金额：
$ 100万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7836639
关键词：
Address Adverse effects Affinity Alzheimer&apos s Disease Area Autologous Binding Biological Assay Calorimetry Cell Therapy Cells Characteristics Collaborations Coronary Arteriosclerosis Development Diabetes Mellitus Disease Dose Embryo Epigenetic Process Fibroblasts Generations Genes Genetic Genetic Materials Histone Deacetylase Inhibitor Histone H3 Histone-Lysine N-Methyltransferase Histones Human In Vitro Inhibitory Concentration 50 Investigation KDM5B gene Lysine Mass Spectrum Analysis Measures Methods Methyltransferase Molecular Mus Neurodegenerative Disorders Parkinson Disease Patients Peptides Peripheral Blood Mononuclear Cell Plasmid Cloning Vector Pluripotent Stem Cells Property Proteins Protocols documentation Publishing Reagent Recombinants Reporting Series Site Somatic Cell Source Specificity Stem Cell Research Stem cells Structure System Technology Testing Time Titrations Undifferentiated Viral Writing analog base clinical application clinically relevant embryonic stem cell healthy volunteer improved in vitro activity induced pluripotent stem cell inhibitor/antagonist meetings mouse model novel patient population peripheral blood pluripotency programs promoter public health relevance self-renewal small molecule stem tool development transcription factor tumor volunteer

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (14): Stem Cells, and meets a few specific Challenge Topics: 14-EB-101: Synthetic Delivery Systems for Generating Pluripotent Stem Cells 14-DK-101: Induced pluripotent stem cells - cellular and humanized mouse models of disease 14-DK-102: Discovery of methods to program stem or progenitor cells 06-GM-102: Chemist/biologist collaborations facilitating tool development A series of studies reported that reprogramming of fully differentiated somatic cells into undifferentiated, pluripotent stem cells could be achieved by introducing a number of transcription factors. These induced pluripotent stem (iPS) cells have almost identical pluripotency to embryonic stem (ES) cells. However, there are serious concerns about any approach in which exogenous genetic factors are introduced into somatic cells, and especially when viral integration or foreign genes, which may induce tumors or other adverse effects, are involved. Although non-viral approaches have recently been developed to generate human iPS cells, the source of cells was limited to human embryonic fibroblasts and therefore could not be used to generate disease-specific iPS cells for research or autologous iPS cells for cell therapy. As these are the main advantages of iPS cells over ES cells, additional sources and safer reprogramming methods are needed. At the time of writing, we have successfully reprogrammed mouse fibroblasts into iPS cells using only small molecules. In addition, we have generated iPS cells from peripheral blood of normal volunteers and coronary artery disease (CAD) patients using viral approaches. Accordingly, in this proposal, we will seek to develop novel methods to generate human iPS cells using peripheral blood as a source in combination with small molecular epigenetic regulators. We anticipate that this study will effect a fundamental change in the method of generating human iPS cells and will have enormous impact on disease investigation and clinical application of iPS cells. PUBLIC HEALTH RELEVANCE: A series of studies reported that reprogramming of fully differentiated somatic cells into undifferentiated, pluripotent stem cells, referred to as induced pluripotent stem (iPS) cells, could be achieved by forced expression of pluripotency-related transcription factors. However, the current technology is limited to the use of genetic material (viral or plasmid vectors) for delivery and fibroblasts for the source of parental cells. Accordingly, in this proposal, we will seek to develop novel methods to generate human iPS cells using combinations of small molecular epigenetic regulators with peripheral blood as the cell source.

描述（由申请人提供）：本申请解决了广泛的挑战领域（14）：干细胞，并满足了一些特定的挑战主题：14-EB-101：用于产生多能干细胞的合成递送系统14-DK-101：诱导多能干细胞-细胞和人源化疾病小鼠模型14-DK-102：06-GM-102：化学家/生物学家合作促进工具开发一系列研究报告称，完全分化的体细胞重新编程为未分化的多能干细胞可以通过引入许多转录因子来实现。这些诱导多能干细胞（iPS）具有与胚胎干细胞（ES）几乎相同的多能性。然而，对于将外源遗传因子引入体细胞的任何方法，特别是当涉及可能诱导肿瘤或其他不良反应的病毒整合或外源基因时，存在严重的担忧。虽然最近已经开发了非病毒方法来产生人iPS细胞，但细胞来源限于人胚胎成纤维细胞，因此不能用于产生用于研究的疾病特异性iPS细胞或用于细胞治疗的自体iPS细胞。由于这些是iPS细胞相对于ES细胞的主要优势，因此需要额外的来源和更安全的重编程方法。在撰写本文时，我们已经成功地使用小分子将小鼠成纤维细胞重编程为iPS细胞。此外，我们已经使用病毒方法从正常志愿者和冠状动脉疾病（CAD）患者的外周血中产生了iPS细胞。因此，在本提案中，我们将寻求开发新的方法，以产生人类iPS细胞使用外周血作为一个来源，结合小分子表观遗传调节剂。我们预计，这项研究将影响人类iPS细胞产生方法的根本性变化，并将对疾病研究和iPS细胞的临床应用产生巨大影响。公共卫生相关性：一系列研究报道，通过强制表达多能性相关转录因子，可以将完全分化的体细胞重编程为未分化的多能干细胞，称为诱导多能干细胞（iPS）。然而，目前的技术仅限于使用遗传物质（病毒或质粒载体）进行递送以及使用成纤维细胞作为亲本细胞的来源。因此，在本提案中，我们将寻求开发新的方法来使用小分子表观遗传调节剂与外周血作为细胞来源的组合来产生人iPS细胞。