Annotated lineage trees of murine development

小鼠发育的注释谱系树

• 批准号: 10472805
• 负责人: Aaron H McKenna
• 金额: $ 147.6万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472805
• 关键词: Biology; Cell Differentiation process; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Development; Event; Genetic Transcription; Goals; Human; Intestines; Maps; Molecular; Mus; Organ; Process; Resolution; Resources; Role; Shapes; System; Technology; Tissues; Translating; Trees; Work; cell transformation; cell type; embryonic stem cell; human disease; improved; innovation; insight; new technology; novel; programs; tool

Understanding the forces that direct cell fate is a central goal of biology. Many fundamental questions remain unanswered and vast tracts of vertebrate development are almost completely unexplored. What are the developmental origins and lineage relationships of cell types? What, where, and when are the key molecular events that underlie cell fate transitions? These questions remain unanswered as we lack the technology to map cell fate in both high-throughput and high-resolution. The overall objective of the proposed work is to develop and apply novel technologies that track and translate the cell fate forces into human-decipherable recordings. Our proposal combines innovative use of new CRISPR systems, molecular recording technologies, and improvements to our established lineage tracing technology to reconstruct high accuracy, annotated lineage trees. We will apply these cell fate technologies in mouse embryonic stem cells (mESCs), where we will track differentiation into various progeny cells, generating both transcriptional and lineage maps describing the probabilistic relationship between intestinal cell types at high-resolution. We will then expand these systems into recording mouse lines, where both molecular and lineage recordings can be captured from terminally differentiated cells. In aggregate, the resulting high-resolution lineage maps and tools will provide new insight into the plasticity of cell fate, and these recording mouse lines will be a valuable resource to the biomedical community. We believe these trailblazing technologies will ultimately spur the development of novel fate modulators with application to human disease.

了解指导细胞命运的力量是生物学的核心目标。许多基本问题仍然存在 尚无答案，大片脊椎动物的发育几乎完全没有被探索过。有哪些 细胞类型的发育起源和谱系关系？关键分子是什么、在哪里、何时 细胞命运转变背后的事件？这些问题仍然没有答案，因为我们缺乏技术 以高通量和高分辨率绘制细胞命运图谱。拟议工作的总体目标是 开发并应用追踪细胞命运力量并将其转化为人类可解读的新技术 录音。我们的提案结合了新 CRISPR 系统、分子记录技术的创新使用， 以及对我们已建立的谱系追踪技术的改进，以重建高精度，带注释 谱系树。我们将把这些细胞命运技术应用到小鼠胚胎干细胞（mESC）中，我们 将跟踪分化为各种子代细胞，生成描述的转录和谱系图 高分辨率肠道细胞类型之间的概率关系。然后我们将扩展这些 系统进入记录小鼠品系，其中分子和谱系记录都可以从 终末分化细胞。总的来说，由此产​​生的高分辨率谱系图和工具将提供 对细胞命运可塑性的新见解，这些记录的小鼠系将成为宝贵的资源 生物医学界。我们相信这些开拓性技术最终将刺激新型技术的发展 命运调节剂应用于人类疾病。