Single cell mapping of developmental trajectories underlying health and disease

描述（由申请人提供）：多细胞生物从单个细胞发育而来，经过许多阶段的增殖和分化，产生大量的祖细胞和终细胞类型。虽然教条将发育定义为一系列离散的步骤，但它实际上是一个连续的过程，其特征是过渡阶段和中间细胞类型，这些尚未被描述。我们建议根据分支轨迹重新构建发育：我们将开发计算算法，使用高维单细胞数据将每个细胞映射到代表发育时间顺序的谱系树中。而不是将细胞分组到这棵树的节点（细胞类型），单个细胞将按照它们的发育时间顺序在连续体中填充分支。因此，每个分支都是一个发育轨迹，代表了细胞状态之间的所有过渡阶段。从本质上讲，将单细胞技术与复杂的计算相结合，将使我们能够为智人做约翰•萨尔斯顿（John Sulston）及其同事为秀丽隐杆线虫所做的事情——构建一个完整而详细的正常发育地图。这张图谱将提供我们体内所有细胞类型的完整目录，以及它们之间的发育关系。最终图谱的详细分辨率将增强发育研究的能力，有助于阐明疾病中发育是如何以及在何处脱轨的，并指导下一代再生医学。

DESCRIPTION (provided by applicant): Multi-cellular organisms develop from a single cell that undergoes many stages of proliferation and differentiation that result in the vast array of progenitor and terminal cell types. While dogma defines development as a series of discrete steps, it is actually a continuous process, characterized by transitional stages and intermediate cell types that have yet to be described. We propose reframing development in terms of branching trajectories: We will develop computational algorithms that use high dimensional single cell data to map each individual cell into a lineage tree representing the chronological order of development. Rather than grouping cells into nodes of this tree (cell types), single cells will fill in the branches in a continuum ordered according to their developmental chronology. Thus, each branch is a developmental trajectory that represents all the transitional stages between cell states. In essence, combining single cell technologies with sophisticated computation will empower us to do for Homo sapiens what John Sulston and colleagues did for C. elegans-to construct a complete and detailed map of normal development. This map will provide both a full catalog of all cell types in our body, as well as the developmental relations between them. The detailed resolution of the resulting map will empower developmental studies, help elucidate how and where development is derailed in disease, and guide the next generation of regenerative medicine.