Development of iPSCs for comparative genomics in primates

灵长类动物比较基因组学 iPSC 的开发

• 批准号: 10189681
• 负责人: Yoav Gilad
• 金额: $ 66.64万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189681
• 关键词: ATAC-seq; Autopsy; Biological Assay; Biological Models; Blood Cells; Cardiac Myocytes; Cell Differentiation process; Cell Line; Cells; Collection; Communities; Comparative Study; Complex; DNA; Data; Data Set; Development; Dimensions; Ectoderm; Endoderm; Evolution; Female; Fibroblasts; Freezing; Funding Opportunities; Gene Expression; Gene Expression Regulation; Genetic; Genetic study; Genomics; Genotype; Germ Layers; Goals; Heart; Hepatocyte; Human; Human Cell Line; Individual; Karyotype determination procedure; Letters; Liver; Macaca mulatta; Mesoderm; Modeling; Molecular; Molecular Biology; Motor Neurons; National Human Genome Research Institute; Nervous system structure; Normal tissue morphology; Pan Genus; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Play; Pongidae; Population Study; Primates; Procedures; Process; Quantitative Reverse Transcriptase PCR; Regulator Genes; Research; Research Personnel; Resolution; Resources; Role; Sampling; Somatic Cell; Surveys; Teratoma; Time; Tissue Differentiation; Tissue Sample; Tissues; Variant; XCL1 gene; biological systems; cell type; comparative; comparative genomics; design; disorder risk; flexibility; functional genomics; genetic architecture; genome integrity; genome-wide; genome-wide analysis; genomic data; human pluripotent stem cell; immunocytochemistry; induced pluripotent stem cell; innovation; insight; male; nonhuman primate; novel strategies; pluripotency; programs; reproductive; response; trait

Abstract This is a new proposal submitted in response to a funding opportunity focused on comparative genomics research (PAR-17-482). The FOA states that NHGRI invites applications for the “development of new comparative genomics research approaches using genomic data types to understand biological systems, networks, and pathways.” And that “high priority will be given to applications that propose innovative and promising approaches to genome-wide and multi-species comparisons.” Differences in gene regulation between humans and other primates may ultimately be used to explain the molecular basis for human-specific traits. While current comparative studies in primates have provided valuable insight into the genetic architecture of gene regulation, they do not provide a flexible framework to study inter-species variation in gene regulation in multiple cell types from the same individuals. In particular, frozen post-mortem tissues are not optimal templates for many functional genomic assays; as a result, we lack data sets that survey multiple dimensions of gene regulatory mechanisms and phenotypes from the same samples. Moreover, because it is rare to collect a large number of tissue samples from the same donor, we have never had the opportunity to study population-level patterns of gene regulation in multiple tissues or cell types derived from the same non-human ape genotype (same donor), and we have not been able to study population-level dynamics of gene regulation, for example, during perturbation. We propose to explore an alternative promising way to move forward. Recent extraordinary advances in molecular biology suggest a way forward. It has now become possible to reprogram somatic cells, such as fibroblasts and several types of blood cells, into a pluripotent state, in which the cells have the capability to both self-replicate indefinitely and to differentiate into any cell type in the body. These reprogrammed (or induced) pluripotent stem cells (iPSCs) can then be directed to differentiate into specific cell types, which can then be studied in detail. The availability of iPSC lines from multiple species could therefore change comparative primate genetics and genomics in a profound way, by allowing us to sidestep traditional limitations on research in primates.

摘要 这是一个新的提案提交的回应资金的机会集中在比较基因组学 研究（PAR-17-482）。FOA指出，NHGRI邀请申请“开发新的 比较基因组学研究方法使用基因组数据类型来了解生物系统， 网络和路径。”并表示，“将优先考虑提出创新和 全基因组和多物种比较的有前途的方法。” 人类和其他灵长类动物之间基因调控的差异最终可能被用来解释 人类特有特征的分子基础。虽然目前对灵长类动物的比较研究提供了 尽管它们对基因调控的遗传结构有着宝贵的洞察力，但它们并没有提供一个灵活的框架， 研究来自同一个体的多种细胞类型中基因调控的物种间差异。特别是， 冷冻的死后组织不是许多功能基因组测定的最佳模板;因此，我们缺乏 数据集调查基因调控机制和表型的多个维度， 样品此外，由于从同一捐赠者身上收集大量组织样本的情况很少见， 我从来没有机会研究多个组织或细胞中基因调控的群体水平模式 类型来自相同的非人类猿基因型（相同的捐赠者），我们还没有能够研究 基因调控的群体水平动态，例如，在扰动期间。 我们建议探索一种有希望的替代办法来向前迈进。最近在以下方面取得的非凡进展： 分子生物学为我们指明了前进的方向现在已经有可能对体细胞进行重新编程，例如 成纤维细胞和几种类型的血细胞，进入多能状态，其中细胞有能力 它们都可以无限地自我复制，并分化成体内的任何细胞类型。重新编程（或 诱导的）多能干细胞（iPSC）然后可以被引导分化成特定的细胞类型，其可以 然后详细研究。因此，来自多个物种的iPSC系的可用性可能会改变。 通过让我们避开传统的限制， 灵长类动物的研究