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Lineage-Specific Mechanisms of Cell Cycle Timing Control

细胞周期计时控制的谱系特异性机制

基本信息

批准号：
10715965
负责人：
Pavak Kirit Shah
金额：
$ 33.81万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-08-31
项目状态：
未结题

项目摘要

Project Summary Decades of studying animal development and in vitro human cell culture have produced many observed tight correlations between the duration of a cell’s cycle and its identity or the fates of its progeny. These links represent a unique opportunity to understand the regulatory relationships between genetic programs of cell fate and the regulation of the cell cycle, both central questions in the study of development, tissue homeostasis, regeneration, and proliferative disorders such as cancer. The nematode Caenorhabditis elegans has been a powerful model in which to study the regulation of cell fate and cell cycle control owing to its genetic tractability, transparent body and embryo, and stereotyped cell lineage. Like most nematodes, C. elegans exhibits eutely or a fixed number of somatic cells in each individual of the same sex. Cell fate in the wild-type animal can thus be determined solely on the basis of its lineage history, for which we have developed extensive tools and approaches for automated reconstruction via 3D timelapse microscopy. Using C. elegans and genetic perturbations that result in transformations of cell fate with its lineage, in combination with automated lineage tracing and spatial transcriptomics approaches, we will investigate the mechanisms by which cell fate influences the duration of a stem cell’s cell cycle as well as the mechanisms by which the duration of a cell cycle can influence cell fate. The work described in this proposal represents a novel approach to considering these links, enabled by our development of lineage tracing technologies and quantitative approaches to discovering structure in cell lineages. Building on this expertise, as well as our imaging resources and collaborations with other tools developers, theorists, and developmental biologists, we will continue to advance the state-of-the-art in lineage- resolved studies of metazoan development. In particular, using our advances in deep learning techniques to enable label-free automated lineage tracing in non-model species in which transgenesis remains impossible or difficult, we will leverage an evolutionary approach to understanding the design principles of gene networks that drive cell fate decisions and control cell cycle progression in the early embryo. Over the next five years we will complete detailed characterizations of co-dependencies between cell cycle timing and cell fate in the C. elegans embryo, create a molecular atlas of cell fate and cell cycle regulation in wild type and mutant C. elegans where cell fate patterning is perturbed, and complete the reconstruction and quantitative analysis of the embryonic lineages of S. stercoralis, P. pacificus, and C. angaria. In the long term, we plan to extend our molecular analyses to these species as well, beginning with C. angaria as an attractive model for studying the evolution of cell fate control networks and their interactions with regulators of the cell cycle. These insights will be of broad value to our understanding of developmental processes, and the resources we will establish will facilitate the work of others on diverse problems in emerging model systems.

项目总结