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NIH Director's Pioneer Award

NIH 院长先锋奖

基本信息

批准号：
7340789
负责人：
MARSHALL S. HORWITZ
金额：
$ 78万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340789
关键词：
Address Adult Affect Algorithms Alleles Anatomy Apoptosis Award Biochemistry Bioinformatics Biology Caenorhabditis elegans Cardiac Myocytes Cell Lineage Cell division Cells Cellular biology Charge Chemicals Chimerism Chromosome abnormality Class Clinic Clinical Collecting Cell Complex Computational Biology Computational Molecular Biology Computers Cultured Cells DNA DNA Sequence DNA biosynthesis Derivation procedure Development Developmental Biology Digestion Dinucleotide Repeats Diploid Cells Diploidy Discipline Disease Doctor of Medicine Doctor of Philosophy Dominant-Negative Mutation Dyes Educational process of instructing Embryo Embryology Embryonic Development Engineering Enzymes Epiblast Epithelial Cells Escherichia coli Evolution Exhibits Facility Construction Funding Category Female Fibroblasts Figs - dietary Foundations Frequencies Funding Future Gene Targeting Generations Genes Genetic Genetic Markers Genetic Polymorphism Genetic Predisposition to Disease Genetic Recombination Genetic Variation Genets Genome Genomics Genotype Germ Layers Goals Growth Health Hematopoietic Neoplasms Hepatocyte Hodgkin Disease Hour Housing Human In Vitro Individual Inherited Insertion Mutation Internal Medicine Interphase Cell Kidney Label Length Link Literature Liver Lobe Magic Mammalian Cell Mammals Maps Measures Medical Genetics Medical Students Medicine Methods Microsatellite Repeats Microscope Microscopic Mismatch Repair Mitosis Mitotic Modeling Molecular Molecular Biology Mosaicism Mus Mutagenesis Mutation Nature Neck Nematoda Neural Crest Neurons Neutropenia New York Numbers Organism Pancytopenia Paper Parotid Gland Pathology Patient Care Peer Review Phylogenetic Analysis Phylogeny Plants Polymerase Chain Reaction Population Population Biology Postdoctoral Fellow Principal Investigator Probability Process Progeria Protein Engineering Publications Publishing Random Allocation Range Rate Reagent Repetitive Sequence Reporting Research Research Personnel Resolution Resources Risk Roentgen Rays Running Sampling Scientist Score Serous Sex Bias Short Tandem Repeat Shoulder Site Solutions Somatic Cell Genetics Somatic Mutation Specialist Specimen Staging Stem cells Stochastic Processes Students Study Section Syndrome Technology Testing Textbooks Time Tissue Sample Tissues Training Training Programs Transfection Transgenic Organisms Trees Tubular formation United States National Institutes of Health Universities Validation Variant Viral Voting Washington Work abstracting asexual authority base blastomere structure cancer cell cancer genetics career cell motility cell type computerized concept day familial Alzheimer disease gene cloning genetic linkage analysis genetic selection genome sequencing improved innovation insertion/deletion mutation mature animal medical schools member microbial migration model development novel novel strategies optimism pluripotency population migration programs reconstruction research study size skills tissue culture trait zygote

项目摘要

Cell fate maps describe how the sequence of cell division, migration, and apoptosis transform a zygote into an adult and are fundamental to understanding stem cell biology. Yet, it is only in the transparent worm C. elegans where tedious microscopic observation of each cell division has allowed for construction of a complete cell fate map. More complex?and opaque?animals prove less yielding. DNA replication, however, inevitably generates somatic mutations. Consequently, multicellular organisms comprise mosaics where most cells acquire unique genomes that are potentially capable of delineating their ancestry. We propose to construct mammalian cell fate maps using a phylogenetic approach to passively retrace embryonic relationships by deducing the order in which mutations have arisen during development. We have found that polyguanine repeat DNA sequences are particularly useful genetic markers, because they frequently change length during mitosis. To demonstrate feasibility, we have used phylogenetics to reconstruct the lineage of cultured mouse NIH3T3 fibroblasts based on mutations affecting the length of polyguanine markers. We have then employed whole genome amplification to genotype polyguanine markers in single cells taken from a mouse and used phylogenetics to infer the developmental relationships of the sampled tissues. Our preliminary results demonstrate the potential of this approach for retrospectively producing a complete mammalian cell fate that, in principle, could describe the developmental lineage of any cell and resolve outstanding questions relevant to stem cell biology.

细胞命运图描述了细胞分裂、迁移和凋亡的顺序如何改变受精卵是理解干细胞生物学的基础。然而，它只存在于透明蠕虫C中。在这种情况下，对每一次细胞分裂的繁琐的显微镜观察允许构建一个完整的细胞命运图更复杂？不透明的？动物证明是不太顺从的。然而DNA复制不可避免地产生体细胞突变。因此，多细胞生物体包括马赛克，其中大多数细胞获得独特的基因组，有可能描绘他们的祖先。我们建议建造哺乳动物细胞命运图使用系统发育方法被动追溯胚胎关系，从而推断出在发育过程中发生突变的顺序。我们发现聚鸟嘌呤重复的DNA序列是特别有用的遗传标记，因为它们经常在过程中改变长度。分裂。为了证明其可行性，我们利用遗传学方法重建了培养小鼠的谱系 NIH3T3成纤维细胞基于影响聚鸟嘌呤标记物长度的突变。然后我们雇用了全基因组扩增以在取自小鼠的单细胞中对聚鸟嘌呤标记进行基因分型，胚胎遗传学来推断取样组织的发育关系。我们的初步结果证明了这种方法用于回顾性地产生完整的哺乳动物细胞命运的潜力，原则上，它可以描述任何细胞的发育谱系，并解决与以下相关的悬而未决的问题：干细胞生物学