Illuminating the chemical biology of stem cell decisions in plant roots

阐明植物根部干细胞决策的化学生物学

• 批准号: 10500929
• 负责人: Alexandra Jazz Dickinson
• 金额: $ 38.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10500929
• 关键词: Anabolism; Atlases; Biochemical; Biology; Cells; Chemicals; Chemistry; Citrates; Decision Making; Defect; Development; Developmental Biology; Disease; Genes; Genetic; Goals; Investigation; Lipids; Maintenance; Maps; Measurement; Measures; Metabolism; Natural regeneration; Organism; Pathway interactions; Pattern; Perception; Plant Roots; Process; Property; Proteins; Regulation; Reporter; Research; Resolution; Retina; Retinaldehyde; Role; Root Tip; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Stress; System; Technology; Tissues; Work; base; cell behavior; insight; mass spectrometric imaging; novel; organ growth; small molecule; stem cell biology; stem cell division; stem cells

Project Summary Small molecules are critical for proper regulation of stem cell behavior in multicellular organisms. Consequently, defects in the biosynthesis, perception, or metabolism of these compounds can cause developmental abnormalities and disease. Despite the critical importance of small molecules, the vast majority of our understanding of their functions is derived from indirect measurements. Typically, studies of small molecule biology are limited to genetic or biochemical approaches that ascribe functional roles to compounds based on the properties of the genes or proteins that interact with these molecules. Alternatively, small molecules are studied using chemical analysis approaches that homogenize bulk tissue and destroy the native context of the signals. High-resolution spatial information is critical in development, where stem cells comprise only a small fraction of the tissue. To enable deeper investigations of chemical regulation of stem cell behavior, my lab will apply technologies capable of directly measuring the localization and activity of small molecules in their native developmental contexts. This work will be done using plant roots, which are a powerful developmental system. Roots store all of their stem cells at the root tip, which generates a developmental gradient that can be examined in a single slice of tissue. My lab will leverage this gradient to investigate the role of small molecules in stem cell decisions. We will map the developmental chemistry of plant roots using mass spectrometry imaging and visualize small molecule interactions with proteins using a synthetic fluorogenic reporter. Metabolite-driven developmental mechanisms will be explored in depth by investigating citrate and retinaldehyde (retinal), two highly conserved metabolites with novel roles in root stem cell divisions and identity. This research will generate: 1) high-spatial resolution atlases detailing the chemical profiles of stem cell decisions, from regeneration to differentiation 2) novel insight into pathways that promote proliferation in stress-resilient stem cell subpopulations and 3) elucidation of dynamic metabolite-driven signaling pathways that regulate stem cell patterning. Our results suggest that there are many small molecules with important developmental roles that await discovery. Conducting research at the intersection of chemistry and developmental biology will provide mechanistic insight into stem cell decisions that would not be possible using a single-disciplinary approach. Accordingly, this work will enrich our understanding of the conserved and divergent principles that govern stem cell patterning, maintenance, divisions, and fate acquisition.

项目概要 小分子对于多细胞生物中干细胞行为的正确调节至关重要。 因此，这些化合物的生物合成、感知或代谢缺陷可能会导致 发育异常和疾病。尽管小分子至关重要，但绝大多数 我们对它们功能的理解来自于间接测量。通常，小分子研究 生物学仅限于遗传或生化方法，这些方法根据化合物的功能赋予化合物 与这些分子相互作用的基因或蛋白质的特性。或者，研究小分子 使用化学分析方法均匀化大块组织并破坏信号的天然背景。 高分辨率空间信息在发育中至关重要，其中干细胞仅占一小部分 组织。为了更深入地研究干细胞行为的化学调节，我的实验室将应用 能够直接测量小分子在其天然状态下的定位和活性的技术 发展背景。这项工作将利用植物根来完成，植物根是一个强大的发育系统。 根将所有干细胞储存在根尖，从而产生可以检查的发育梯度 在单片组织中。我的实验室将利用这种梯度来研究小分子在干细胞中的作用 决定。我们将使用质谱成像绘制植物根部的发育化学图谱并进行可视化 使用合成荧光报告基因与蛋白质进行小分子相互作用。代谢驱动的发育 将通过研究柠檬酸盐和视黄醛（视黄醛）这两种高度保守的物质来深入探讨机制。 在根干细胞分裂和身份中具有新作用的代谢物。这项研究将产生：1）高空间 详细描述干细胞从再生到分化的化学特征的分辨率图谱 2) 对促进抗应激干细胞亚群增殖途径的新见解和 3) 阐明调节干细胞模式的动态代谢物驱动的信号通路。我们的成果 表明有许多具有重要发育作用的小分子有待发现。指挥 化学和发育生物学交叉点的研究将为干细胞提供机制性的见解 使用单一学科方法不可能做出细胞决策。因此，这项工作将丰富 我们对控制干细胞模式、维护的保守和不同原则的理解， 分裂，以及命运的获得。