Stem Cells

理由：目前的生物医学研究主要是将基因和环境与功能联系起来的范式。通过全基因组关联分析，人类遗传学的最新进展大大加快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（即功能基因组学）的挑战。在过去，大多数功能基因组学工作是通过使用基因操作来建立动物模型，这些模型携带与人类疾病相同的基因突变。然而，这种方法往往是费力的，更重要的是，有多少人类疾病可以在这些动物模型中重现，仍然是一个巨大的不确定性。然而，直到最近，还没有可行的替代办法。人类多能胚胎干细胞（hESCs）和人类诱导多能干细胞（h-iPSCs）的建立正开始彻底改变功能基因组学、疾病建模、疾病机制研究、药物筛选和新治疗干预开发的方式。特别是，通过iPSC技术，将患者特异性细胞用作研究对象，我们终于能够利用自然已经产生的遗传操作，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。为了利用这一不断发展的技术，IDDRC的研究人员表示需要集中专业知识、协调和帮助干细胞/iPSC的产生、维持、谱系分化和标准化，目的是建立与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，这成为建立这个新的干细胞核心的动力，我们在加州大学洛杉矶分校拥有所有必要的专业知识来提供这样的服务。

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.