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.

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促进工具开发一系列研究报告说，将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。这些诱导的多能干（IPS）细胞与胚胎（ES）细胞具有几乎相同的多能性。然而，人们对将外源遗传因素引入体细胞的任何方法都有严重的担忧，尤其是当涉及肿瘤或其他不良影响的病毒整合或外源基因时。尽管最近已经开发出非病毒方法来产生人IPS细胞，但细胞的来源仅限于人类胚胎成纤维细胞，因此不能用于生成疾病特异性的IPS细胞进行研究或自体IPS细胞进行细胞疗法。由于这些是IPS细胞比ES细胞的主要优点，因此需要其他来源和更安全的重编程方法。在写作时，我们仅使用小分子成功地将小鼠成纤维细胞重新编程为IPS细胞。此外，我们使用病毒方法从正常志愿者和冠状动脉疾病（CAD）患者的外周血产生了IPS细胞。因此，在此提案中，我们将寻求开发新的方法来使用外周血作为来源与小分子表观遗传调节剂结合使用。我们预计这项研究将影响产生人IPS细胞的方法的根本变化，并将对IPS细胞的疾病研究和临床应用产生巨大影响。公共卫生相关性：一系列研究报告说，可以通过强制强迫表达多能相关的转录因子来实现完全分化的体细胞为未分化的多能干细胞（称为诱导多能干（IPS）细胞）的重编程。但是，当前的技术仅限于使用遗传物质（病毒或质粒载体）用于递送的遗传材料和父母细胞来源的成纤维细胞。因此，在此提案中，我们将寻求开发新的方法来使用与外周血作为细胞源的小分子表观遗传调节剂的组合产生人IPS细胞。