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: 10514213
• 负责人: Yoav Gilad
• 金额: $ 13.12万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514213
• 关键词: Autopsy; Biological Assay; Biological Models; Blood Cells; Cell Line; Cells; Communities; Comparative Study; Data Set; Development; Dimensions; Fibroblasts; Freezing; Funding Opportunities; Gene Expression Regulation; Genetic; Genomics; Genotype; Human; Individual; Macaca mulatta; Molecular; Molecular Biology; National Human Genome Research Institute; Pan Genus; Pathway interactions; Pattern; Phenotype; Pongidae; Population Study; Primates; Regulator Genes; Research; Sampling; Somatic Cell; Surveys; Tissue Sample; Tissues; Variant; biological systems; cell type; comparative; comparative genomics; flexibility; functional genomics; genetic architecture; genome-wide; genomic data; human pluripotent stem cell; induced pluripotent stem cell; innovation; insight; 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 这是针对比较基因组学资助机会而提交的新提案 研究 (PAR-17-482) FOA 指出 NHGRI 邀请“开发新产品”的申请。 使用基因组数据类型来理解生物系统的比较基因组学研究方法， 网络和途径。”并且“将高度优先考虑提出创新和 进行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可以用来解释 目前对灵长类动物的比较研究已经提供了人类特异性特征的分子基础。 对基因调控的遗传结构具有宝贵的见解，但它们没有提供灵活的框架 研究来自同一个体的多种细胞类型的基因调控的种间变异。 冷冻的死后组织并不是许多功能基因组学的最佳模板，因此我们缺乏检测方法； 调查基因调控机制和表型多个维度的数据集 此外，由于从同一捐献者那里收集大量组织样本的情况很少见，因此我们 从未有机会研究多个组织或细胞中基因调控的群体水平模式 源自相同非人类猿基因型（同一供体）的类型，我们无法研究 基因调控的群体水平动态，例如，在扰动期间。 我们建议探索另一种有希望的前进方式。 分子生物学提出了一条前进的道路，现在已经可以重新编程体细胞，例如 成纤维细胞和几种类型的血细胞进入多能状态，其中细胞有能力 两者都能无限地自我复制并分化成体内的任何细胞类型。 然后可以引导诱导的）多能干细胞（iPSC）分化为特定的细胞类型，这可以 因此，来自多个物种的 iPSC 系的可用性可能会发生变化。 比较灵长类遗传学和基因组学，使我们能够绕过传统的局限性 关于灵长类动物的研究。