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: 10428553
• 负责人: Yoav Gilad
• 金额: $ 60.4万
• 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/10428553
• 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.

抽象的 这是一项新提议，以回应针对比较基因组学的资金机会 研究（PAR-17-482）。 FOA指出，NHGRI邀请申请“开发新的 使用基因组数据类型的比较基因组学研究方法来了解生物系统， 网络和途径。”和“将对提出创新和提出创新的应用程序的高度优先级 对全基因组和多种物种比较的有前途的方法。” 人类与其他初学性之间基因调节的差异最终可以用来解释 人类特异性性状的分子基础。虽然目前的初级比较研究已提供 对基因调节的遗传结构的有价值的洞察力，它们不提供灵活的框架 研究来自同一个体的多种细胞类型的基因调节的种间变化。尤其， 冷冻的验尸时机不是许多功能基因组测定的最佳模板。结果，我们缺乏 调查基因调节机制和表型的多个维度的数据集 样品。而且，由于很少从同一供体收集大量的组织样品，所以我们 从来没有机会在多个时间或细胞中研究基因调节的人群水平模式 源自同一非人类APE基因型（同一供体）的类型，我们无法研究 基因调控的种群级动力学，例如，在扰动过程中。 我们建议探索一种前进的另一种有希望的方式。最近的非凡进步 分子生物学提出了前进的道路。现在已经有可能重新编程体细胞，例如 成纤维细胞和几种类型的血细胞，进入多能状态，其中细胞具有能力 两者都可以无限期地重复进行，并分化为体内任何细胞类型。这些重新编程（或 诱导的）多能干细胞（IPSC）可以被定向到特定的细胞类型中，这可以 然后详细研究。因此，来自多个物种的IPSC线的可用性可能会改变 通过允许我们避开传统限制，以深刻的方式进行比较的主要遗传学和基因组学 关于私人研究。