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: 9908114
• 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/9908114
• 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.

项目总结/文摘