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.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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