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Genetically Diverse Mouse Embryonic Stem Cells: A Platform for Cellular Systems Genetics

遗传多样性的小鼠胚胎干细胞：细胞系统遗传学平台

基本信息

批准号：
10360434
负责人：
Christopher Lee Baker
金额：
$ 81.63万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360434
关键词：
Adoption Allelic Imbalance Biological Assay Biology Cell Line Cell Shape Cell Therapy Cells Chromosome Mapping Communities Confounding Factors (Epidemiology)Credentialing Data Data Analyses Development ES Cell Line Environment Exhibits Gene Expression Gene Frequency Generations Genes Genetic Genetic Research Genetic Transcription Genetic Variation Genetic study Genome Genotype Goals Gold Grant Heterogeneity Human In Vitro Inbred Strain Inbred Strains Mice Individual Laboratory mice Maps Masks Mesoderm Modeling Mus Mutant Strains Mice Online Systems Organoids Pathway interactions Patients Pharmacogenomics Phenotype Pilot Projects Pluripotent Stem Cells Population Publishing Quantitative Trait Loci Regenerative Medicine Reporting Reproducibility Research Resolution Resources Role Route SNP genotyping Sampling Source Structure Sum System Systems Development Testing The Jackson Laboratory Toxicogenomics Validation Variant Visualization software base cell type cohort cost effective data integration design directed differentiation embryonic stem cell experimental study gene environment interaction gene regulatory network genetic resource genomic locus human disease human pluripotent stem cell human stem cells interactive tool molecular phenotype novel personalized medicine phenotypic data pluripotency precision medicine predictive modeling predictive test rational design response reverse genetics searchable database single-cell RNA sequencing stem cell biology stem cells tool transcriptome sequencing

项目摘要

PROJECT SUMMARY The objective of this application is to generate a thoroughly-validated panel of genetically diverse mouse embryonic stem cells (mESC) that will enable widespread adoption of cellular systems genetics. Phenotypic variation, manifesting as heterogeneity in cell state, represents a significant challenge for realizing the full promise of individualized, cell-based therapies, regenerative medicine. But phenotypic variation in genetically diverse stem cells also presents an opportunity for the advancement of large scale, cellular screens of gene by environment interactions (e.g. pharmacogenomics, toxicogenomics). A variety of approaches are beginning to identify the networks that drive cell state transitions, but these efforts have largely focused on bulk assays, which do not provide sufficient resolution of cell state heterogeneity, and mask the contribution of underlying genetic variation on rare cell types. Moreover, genetic studies using human pluripotent stem cells are largely limited to testing common variants due to low allele frequencies and imbalanced population structure requiring prohibitively large samples and impeding identification of core regulatory networks with high power and resolution. Therefore, we currently lack a thorough understanding of the genes and mechanisms that underlie phenotypic variation in pluripotent stem cells. The Diversity Outbred (DO) mouse population at The Jackson Laboratory is genetically defined, diverse, and presents a singular, cost-effective opportunity to systematically investigate heterogeneity in mammalian pluripotency. Our pilot studies using DO mESCs establish the feasibility of identifying regulatory loci at high power and resolution, as well as networks conserved in mice and humans that regulate cell state transitions. In Aim 1, we will create a reference mapping panel of 300 DO mESC lines that will serve as a gold standard resource for cellular systems genetics. This panel will be fully credentialed and banked for broad availability through The Jackson Laboratory / Mutant Mouse Resource and Research Centers (MMRRC). In Aim 2, we will determine at the single cell level the transcriptional networks that regulate cell state transitions in vitro through the early stages of differentiation to mesoderm in a representative subset of 144 lines. In Aim 3, we will map quantitative trait loci (QTL) that underlie variation in cell state-specific gene expression and in the distribution of cell states in a population. In addition, we will build and test models based on polygenic scores that can predict differentiation propensity from genotype. Finally, a web-based searchable database of expression phenotypes and interactive tools for visualization of cell composition and eQTL will be made publicly available to support community queries and hypothesis generation. In sum, we will produce a resource of cell lines and gene expression data for the research community that will spur new discoveries in regenerative medicine, pharmacogenomics, and toxicogenomics.

项目总结