Systems analysis of cell type differentiation in xenopus development

非洲爪蟾发育中细胞类型分化的系统分析

• 批准号: 8341917
• 负责人: MARC Wallace KIRSCHNER
• 金额: $ 65.63万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8341917
• 关键词: Address; Adult; Affect; Animal Cap; Anterior; Bayesian Method; Beta Cell; Biological; Biological Assay; Biological Models; Cell Differentiation process; Cells; Child; Childhood; Collaborations; Collection; Complex; Data; Data Set; Defect; Detection; Development; Developmental Process; Dorsal; Ectoderm Cell; Elements; Embryo; Embryology; Embryonic Development; Endoderm; Endoderm Cell; Engineering; Epidermis; Event; Fertilization; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; Growth; Growth Factor; Hour; Human; Individual; Knowledge; Lateral; Lateral Mesoderm; Lead; Learning; Maps; Mass Spectrum Analysis; Mesoderm; Mesoderm Cell; Messenger RNA; Methods; Modeling; Modification; Molecular; Nodal; Pancreas; Partner in relationship; Pathway Analysis; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Post-Translational Protein Processing; Procedures; Process; Proteins; Proteome; Proteomics; RNA; Regenerative Medicine; Resolution; Series; Signal Pathway; Signal Transduction; Staging; Structure; System; Systems Analysis; Systems Biology; Techniques; Technology; Time; Tissues; Transcript; Translations; Undifferentiated; Variant; Vertebrates; Xenopus; Xenopus laevis; base; blastomere structure; cell type; computer based statistical methods; egg; human disease; improved; in vivo; insight; progenitor; protein expression; reconstruction; relating to nervous system; stem cell biology; tool; transcriptomics; xenopus development

DESCRIPTION (provided by applicant): We propose to advance a systems biology framework for an integrative understanding of the signaling and transcriptional events in early vertebrate embryonic development leading to major ectodermal, mesodermal, and endodermal cell types, using the Xenopus laevis model system. Controlled manipulation of three signaling pathways, Bmp, Nodal, and Wnt, will be used to drive multipotent embryonic cells in different well-defined developmental directions. We will characterize each of the endpoint cell types and many intermediates, providing a step- by-step analysis of the changes in protein and mRNA levels as a cell makes fate choices. Our team is a close collaboration between two expert embryologists/cell biologists (Kirschner and Gerhart) with an expert in systematic analysis and statistical inference (Peshkin) and an expert in proteomic mass spectrometry (Gygi). Our recently developed methods will allow us to reach unprecedented levels of detection and quantification of proteins, protein post-translational modifications, and mRNA transcripts. The large size of Xenopus eggs and embryos will also permit single-cell studies in some cases. We hypothesize that high quality proteomic profiling of early development will produce new key insights into developmental signaling pathways. Our dataset will provide an unprecedented degree of systems-level knowledge on the localization- and time-dependent actions of proteins in early vertebrate development, in cells fated to become different cell types. This information will be new for many biological problems, and revolutionary for embryology. Our suite of methods will allow rapid profiling of the effect of developmental signals on key pathways, and on vertebrate embryonic development in general. These key pathways are also important in later developmental processes, in childhood development, tissue and cell turnover in adults, and in approaches to regenerative medicine based on stem cell biology. They are also largely conserved across species, promising rapid transfer from the model system to human patients. We expect that these data will inform on heritable defects in human embryos and children in new ways. PUBLIC HEALTH RELEVANCE: We will apply and develop modern genomic tools focused the embryonic development of cell types in the vertebrate embryo with the goal of understanding and ultimately controlling pathways for cell differentiation. Such studies could facilitate the development of procedures to direct cell differentiation in ways that would ultimately contribute to regenerative medicine in the treatment of important human diseases.

描述（由申请人提供）：我们建议推进一个系统生物学框架，以综合理解早期脊椎动物胚胎发育中导致主要外胚层、中胚层和内胚层细胞类型的信号和转录事件，使用非洲爪蟾模型系统。Bmp、Nodal和Wnt三种信号通路的控制将用于驱动多能胚胎细胞向不同明确的发育方向发展。我们将描述每一种终点细胞类型和许多中间产物，提供蛋白质和mRNA水平在细胞做出命运选择时的变化的逐步分析。我们的团队是由两位胚胎学家/细胞生物学家（Kirschner和Gerhart）与一位系统分析和统计推断专家（Peshkin）和一位蛋白质组质谱专家（Gygi）密切合作组成的。我们最近开发的方法将使我们能够达到前所未有的蛋白质，蛋白质翻译后修饰和mRNA转录物的检测和定量水平。爪蟾卵和胚胎的大尺寸也允许在某些情况下进行单细胞研究。我们假设，高质量的早期发育蛋白质组学分析将为发育信号通路提供新的关键见解。我们的数据集将提供前所未有的系统级知识，了解蛋白质在早期脊椎动物发育过程中的定位和时间依赖作用，以及注定成为不同细胞类型的细胞。这一信息对许多生物学问题来说都是新的，对胚胎学来说也是革命性的。我们的方法套件将允许快速分析发育信号对关键途径的影响，以及对脊椎动物胚胎发育的影响。这些关键途径在后期发育过程、儿童发育、成人组织和细胞更新以及基于干细胞生物学的再生医学方法中也很重要。它们也在很大程度上跨物种保守，有望从模型系统快速转移到人类患者身上。我们期望这些数据将以新的方式为人类胚胎和儿童的遗传缺陷提供信息。