Regulatory circuitry and mechanisms controlling cell fate in C. elegans

控制线虫细胞命运的调节电路和机制

• 批准号: 10395484
• 负责人: Iva S Greenwald
• 金额: $ 58.35万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395484
• 关键词: Address; CRISPR/Cas technology; Caenorhabditis elegans; Cell Communication; Cells; Congenital Abnormality; Cues; Data Collection; Development; Developmental Biology; Diagnostic; Disease; Engineering; Epidermal Growth Factor Receptor; Fostering; Foundations; Gene Expression; Genetic; Gonadal structure; Health; Human; Lobular Neoplasia; Malignant Neoplasms; Medicine; Methods; Microfluidics; Molecular; Monitor; Pattern; Physiological; Population; Regulation; Signal Pathway; Signal Transduction; System; Technology; Therapeutic; Time; Vulva; Work; base; cell fate specification; gene function; genetic analysis; genetic approach; human disease; insight; life history; notch protein; personalized medicine; serial imaging; temporal measurement; tool

Project Summary/Abstract This proposal addresses how cells communicate with each other to control development by elucidating the signaling components, modulators and mechanisms that govern cell-cell interactions. Understanding the underlying genetic circuitry and molecular mechanisms is critical, because aberrant activity of these same signaling pathways have profound effects on human health, most notably as causal agents of cancer, congenital defects and diverse physiological disorders. Regulating signaling appropriately—in space or cell population, in time, strength or duration, or in combination with other signaling inputs—is thus crucial both for normal development and for insight into human disease. This proposal builds on foundational work on two key developmental paradigms in C. elegans: (i) specification of alternative cell fates by LIN- 12/Notch signaling in the gonad and (ii) the integration of LIN-12/Notch and EGFR-Ras-ERK signaling to pattern three distinct fates in the vulva. Although each paradigm has unique attributes, they provide a unified platform for elucidating regulatory circuitry and mechanisms underlying cell fate decisions and the function and regulation of major, conserved signaling systems. These C. elegans paradigms have a distinguished record of fostering discoveries that are directly applicable to basic human developmental biology and medicine, and a major reason is that they are especially amenable to genetic analysis. The proposed work will utilize a combination of classical genetic approaches and CRISPR/Cas9-engineering and other technologies to manipulate and monitor gene function, as well new microfluidic-based methods for longitudinal imaging and automated data collection that allows unprecedented cellular precision and temporal resolution in analyzing cell fate choice, gene expression, and signaling dynamics. The work will address three key gaps in understanding: (i) the relationship between signaling dynamics and cell fate specification, (ii) the regulatory circuitry and mechanisms that enable precise and robust spatial patterning, and (iii) the regulation of developmental progression through integrating life history and environmental cues with spatial patterning. The identification of mechanisms by which major, conserved signaling systems are regulated and integrated with each other is increasingly important in the era of personalized medicine and the deeper understanding of developmental mechanism we will achieve through these studies will be potentially applicable to developing diagnostic and therapeutic tools for human disease.

项目摘要/摘要 该建议介绍了细胞如何通过 阐明控制细胞细胞的信号传导组件，调节剂和机制 互动。了解潜在的遗传回路和分子机制至关重要， 因为这些相同信号通路的异常活动对人有深远的影响 健康，最著名的是癌症的因果因素，先天性缺陷和潜水员生理学 疾病。适当地调节信号 - 在空间或细胞种群中，及时，强度或 持续时间，或与其他信号输入结合使用 - 因此，正常都至关重要 发展并洞悉人类疾病。该提议以基础工作为基础 秀丽隐杆线虫中的两个关键发育范式：（i）lin-规范替代细胞命运 GONAD中的12/Notch信号传导，（ii）Lin-12/Notch和EGFR-RAS-ERK的整合 向图案发出信号，外阴中的三个不同的命运。虽然每个范式都有独特的 属性，它们为阐明调节电路和机制提供了统一的平台 基本细胞脂肪决策以及主要信号的功能和调节 系统。这些秀丽隐杆线虫范式具有杰出的寄养发现记录 直接适用于基本的人类发育生物学和医学，这是主要原因 是它们特别适合遗传分析。拟议的工作将利用 古典遗传方法与CRISPR/CAS9工程和其他的组合 操纵和监测基因功能的技术以及新的基于微流体的方法 用于纵向成像和自动数据收集，允许前所未有的细胞 分析的细胞命运选择，基因表达和信号传导中的精度和临时分辨率 动力学。这项工作将解决理解的三个关键差距：（i） 信号传导动力学和细胞脂肪规范，（ii）调节电路和机制 启用精度和稳健的空间图案，以及（iii）发育进展的调节 通过将生活历史和环境线索与空间图案整合在一起。标识 主要组成信号系统的机制，并与 在个性化医学时代，彼此越来越重要 了解我们将通过这些研究实现的发展机制将是 可能适用于开发人类疾病的诊断和治疗工具。