Stem Cells

干细胞

• 批准号: 8382154
• 负责人: HARLEY IAN KORNBLUM
• 金额: $ 14.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382154
• 关键词: Accounting; Adult; Animal Model; Astrocytes; Biomedical Research; Brain Neoplasms; Cell Culture Techniques; Cell model; Cells; Childhood Brain Neoplasm; Clinical; Collection; Communities; Comparative Study; Consensus; Derivation procedure; Development; Developmental Disabilities; Developmental Process; Disease; Disease model; Elements; Embryo; Ensure; Environment; Explosion; Functional disorder; Gene Expression; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Human; Human Genetics; Ice; Intellectual functioning disability; Joints; Knowledge; Link; Maintenance; Malignant Neoplasms; Mental Retardation and Developmental Disabilities Research Centers; Methodology; Mission; Molecular; Molecular Models; Mus; Mutation; Mutation Spectra; Nature; Neuroglia; Neurons; Oligodendroglia; Oncogenic; Pathologic Processes; Pathway interactions; Patients; Phenotype; Pluripotent Stem Cells; Population; Preclinical Drug Evaluation; Process; Production; Property; Quality Control; RNA; Rattus; Reproducibility; Research; Research Design; Research Personnel; Resected; Resources; Sampling; Scientist; Source; Specimen; Standardization; Stem cells; Synapses; Technology; The Cancer Genome Atlas; The Sun; Time; Tumor Stem Cells; Uncertainty; Variant; Work; base; developmental disease; disease phenotype; driving force; effective therapy; embryonic stem cell; experience; functional genomics; gene discovery; gene function; genetic manipulation; genome sequencing; genome wide association study; human disease; human embryonic stem cell; in vitro Model; induced pluripotent stem cell; interest; molecular modeling; mortality; nerve stem cell; novel; novel therapeutic intervention; stem cell differentiation; tool; tumor; tumorigenic

Rationale: Biomedical research at the present time is dominated by the paradigm of linking genes and environment to function. Recent advances in human genetics through genome-wide association analyses have greatly accelerated the disease gene discovery process. However, in this post-genome sequencing era, we are faced with the challenge of determining the cellular and organismal functions of these genes and how gene dysfunction leads or contributes to the phenotype of the disease (i.e. functional genomics). In the past, most functional genomics work was carried out through using genetic manipulations to build animal models that carry the same mutations in genes as in human diseases. However, this approach is often laborious and, more importantly, how much of the human disease can be recapitulated in those animal models remains a huge uncertainty. However, until recently, no viable alternative approaches were available. The establishment of human pluripotent embryonic stem cells (hESCs) and human induced pluripotent stem cells (h-iPSCs) is beginning to revolutionize the way to approach functional genomics, disease modeling, disease mechanistic studies, drug screening, and development of novel therapeutic interventions. Particularly, with iPSC technology, where patient-specific cells are utilized as research objects, we are finally able to utilize the genetic manipulations that nature has already generated, as well as taking into account the enormous genetic predispositions/variations that exist in the population, to develop population stratified or even personalized effective therapies. To utilize this expanding technology, IDDRC investigators have expressed the need for centralized expertise, coordination, and help with stem cell/iPSC generation, maintenance, lineage differentiation, and standardization, with the aims of building novel cellular and molecular models relevant to IDD. A strong internal consensus within the UCLA IDDRC community about the importance of these cells has become the driving force for the establishing of this new Stem Cell Core, and we have all the required expertise in place at UCLA to provide such a sen/ice. A number of IDDRC investigators are studying pediatric brain tumors with the goal of alleviating the mortality and developmental disability associated with them. In an analogous fashion to the explosion in knowledge of the genotype/phenotype relationship in genetically-based developmental disorders, similar breakthroughs are being made in the study of cancer. The Cancer Genome Atlas (TCGA) project is delineating the spectrum of mutations present in human brain tumors (http://cancergenome.nih.gov/), and there has been a large increase in the understanding of oncogenic pathways in brain tumors. However, similar to genetic developmental disorders, the study of pediatric brain tumors has been hampered by the lack of appropriate in vitro models. The recent discovery of stem cell-like cells in brain tumors (Hemmati et al., 2003), including pediatric brain tumors and the ability to propagate these highly relevant, tumorigenic cultures permits the study of molecular processes that drive these cells, the correlation of genotype and phenotype, and the development of novel potential therapies. The purpose of this new Core is to provide excellent technical support and expertise in the generation, characterization, maintenance, expansion, and lineage differentiation of human pluripotent stem cells including primarily IPSCs from patients as well as previously established hESCs (as controls and for comparative studies). In addition, due to the additional joint interest among our IDDRC investigators on brain tumors, methodologies of growing brain tumor stem cells, together with prepared tumor stem cell cultures from resected tumor specimens will also be provided by the core. In addition to the rationale outlined above, there are additional reasons for establishing a Stem Cell Core within the IDDRC. Previously, based on the consensus among scientists conducting hESC work, researchers worid-wide submitted RNA samples from their brew of cultured hESCs and a large scale gene expression array analysis was carried out. The results indicated that the most important element that accounts for variation among the different samples depended upon who had been handling the cells. Different investigators handle cells differently, which probably changed the molecular/cellular properties of the cells. Therefore, a centralized effort for stem cell production, characterization, maintenance, and expansion is very beneficial for subsequent research. This Core will provide standardization and quality control of the cells to ensure reproducibility and stability of the cell sources. In addition, based on many years of experience in studying neural stem cell (NSC), differentiation from various sources including NSCs derived from developing mouse, rat, and human embryos and adult, NSCs derived from mouse and human ESCs, as well as NSCs derived from mouse and human iPSCs, Drs. Sun and Zeng are well-situated to provide expertise concerning how to effectively differentiate human iPSCs and human ESCs first into expandable NSCs, and then subsequently into functional neurons that form synaptic network and glial cells (i.e., astrocytes and oligodendrocytes). Finally, Dr. Kornblum is among the earliest investigators studying brain tumor stem cells. He and Dr. Le Belle are very familiar with the sample (brain tumor) collection as well as the subsequent derivation of brain tumor stem cell cultures. It would be difficult for an average scientist in the IDDRC to interact with the clinicians and to have access to clinical samples in a regulated manner. Drs. Kornblum and Le Belle represent an enormous resource for the IDDRC community and will be able to handle the technical or scientific issues related to brain tumor stem cells, as well as distribution of brain tumor stem cells for many types of studies.

理由：目前的生物医学研究以将基因和环境与功能联系起来的范式为主导。通过全基因组关联分析，人类遗传学的最新进展极大地加速了疾病基因的发现过程。然而，在这个后基因组测序时代，我们面临着确定这些基因的细胞和有机体功能以及基因功能障碍如何导致或促成疾病表型的挑战（即功能基因组学）。过去，大多数功能基因组学工作是通过使用基因操作来建立携带与人类疾病相同的基因突变的动物模型来进行的。然而，这种方法通常很费力，更重要的是，在这些动物模型中可以重现多少人类疾病仍然存在巨大的不确定性。然而，直到最近，还没有可行的替代方法。人类多能胚胎干细胞（hESC）和人类诱导多能干细胞（h-iPSC）的建立正在开始彻底改变功能基因组学、疾病建模、疾病机制研究、药物筛选和新型治疗干预措施开发的方式。特别是，通过 iPSC 技术，利用患者特异性细胞作为研究对象，我们最终能够利用大自然已经产生的基因操作，并考虑到人群中存在的巨大遗传倾向/变异，开发人群分层甚至个性化的有效疗法。为了利用这一不断扩展的技术，IDDRC 研究人员表示需要集中专业知识、协调并帮助干细胞/iPSC 生成、维护、谱系分化和标准化，以建立与 IDD 相关的新型细胞和分子模型。加州大学洛杉矶分校 IDDRC 社区内部对这些细胞的重要性达成了强烈的共识，这已成为建立这种新干细胞核心的驱动力，并且我们在加州大学洛杉矶分校拥有提供此类服务所需的所有专业知识。 许多 IDDRC 研究人员正在研究儿童脑肿瘤，目的是减轻对儿童脑肿瘤的影响。 与之相关的死亡率和发育障碍。与基于遗传的发育障碍的基因型/表型关系知识的爆炸式增长类似，癌症研究也取得了类似的突破。癌症基因组图谱 (TCGA) 项目正在描绘人类脑肿瘤中存在的突变谱 (http://cancergenome.nih.gov/)，并且人们对脑肿瘤致癌途径的了解已大大增加。然而，与遗传发育障碍类似，儿童脑肿瘤的研究因缺乏适当的体外模型而受到阻碍。最近在脑肿瘤（包括儿童脑肿瘤）中发现了干细胞样细胞（Hemmati 等，2003），并且能够繁殖这些高度相关的致瘤培养物，从而可以研究驱动这些细胞的分子过程，基因型和表型，以及新的潜在疗法的开发。 这个新核心的目的是在人类多能干细胞的生成、表征、维护、扩增和谱系分化方面提供卓越的技术支持和专业知识，主要包括来自患者的 IPSC 以及先前建立的 hESC（作为对照和用于比较研究） ）。此外，由于我们的 IDDRC 研究人员对脑肿瘤的共同兴趣，核心也将提供生长脑肿瘤干细胞的方法，以及从切除的肿瘤标本中制备的肿瘤干细胞培养物。 除了上述理由外，在 IDDRC 内建立干细胞核心还有其他原因。此前，基于进行 hESC 工作的科学家们达成的共识，世界各地的研究人员提交了来自培养的 hESC 的 RNA 样本，并进行了大规模基因表达阵列分析。结果表明，造成不同样品之间差异的最重要因素取决于处理细胞的人。不同的研究人员以不同的方式处理细胞，这可能改变了细胞的分子/细胞特性。因此，集中精力进行干细胞的生产、表征、维护和扩增对于后续的研究非常有利。 研究。该核心将为细胞提供标准化和质量控制，以确保细胞来源的可重复性和稳定性。此外，基于多年研究神经干细胞（NSC）的经验，从各种来源分化，包括来自发育中的小鼠、大鼠和人类胚胎和成体的NSCs，来自小鼠和人类ESCs的NSCs，以及来自小鼠、大鼠和人类胚胎干细胞的NSCs。来自小鼠和人类 iPSC，博士。 Sun 和 Zeng 非常适合提供有关如何有效地将人类 iPSC 和人类 ESC 首先分化为可扩展 NSC，然后分化为形成突触网络和神经胶质细胞（即星形胶质细胞和少突胶质细胞）的功能神经元的专业知识。最后，科恩布鲁姆博士是最早研究脑肿瘤干细胞的研究人员之一。他和 Le Belle 博士非常熟悉样本（脑肿瘤）的采集以及随后脑肿瘤干细胞培养物的衍生。 IDDRC 的普通科学家很难与临床医生互动并以受监管的方式获取临床样本。博士。 Kornblum 和 Le Belle 代表了 IDDRC 社区的巨大资源，将能够处理与脑肿瘤干细胞相关的技术或科学问题，以及用于多种类型研究的脑肿瘤干细胞的分布。