Systems biology of MAPK signaling in early drosophila embryo

果蝇早期胚胎 MAPK 信号传导的系统生物学

• 批准号: 8332799
• 负责人: Stanislav Y. Shvartsman
• 金额: $ 34.13万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332799
• 关键词: Adult; Area; Binding; Biochemical; Biochemistry; Biological Assay; Cell Differentiation process; Cell physiology; Complex; Computer Analysis; Development; Disease; Drosophila genus; Drug Delivery Systems; Drug Formulations; Embryo; Enzymes; Gene Expression; Genes; Genetic; Genetic Models; Lead; Malignant Neoplasms; Mitogen-Activated Protein Kinases; Modeling; Molecular; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation; Positioning Attribute; Publishing; Regulation; Relative (related person); Reporter; Role; Signal Pathway; Signal Transduction; Specificity; System; Systems Analysis; Systems Biology; Testing; Therapeutic; Tissues; Work; base; cell growth; design; enzyme substrate; human disease; in vivo; innovation; insight; mathematical model; research study; spatial integration; tool; transcription factor

DESCRIPTION (provided by applicant): The Mitogen Activated Protein Kinase (MAPK) signaling pathway is a critical regulator of cellular processes in adult and developing tissues. Deregulated MAPK signaling is associated with a number of diseases, which makes it a key drug target in multiple therapeutic areas. Given a large number of components and levels of regulation within this important pathway, understanding and controlling its function is essentially impossible without quantitative experiments, mathematical modeling, and computational analysis. The terminal patterning system in the early Drosophila embryo is ideally suited for this purpose because of its relative anatomical simplicity and the availability of a large number of genetic tools for the manipulation of MAPK regulators and substrates. We have developed quantitative assays for the in vivo analysis of MAPK phosphorylation and signaling in the terminal patterning system. Based on these assays, in our recently published work we formulated a model according to which the spatial pattern of MAPK signaling in the early embryo is controlled by an enzyme-substrate competition network. Specifically, we proposed that MAPK substrates compete among themselves and with the MAPK phosphatase for binding to the activated MAPK. In addition, we proposed that MAPK substrate competition influences not only the MAPK pathway, but also its interaction with other signaling systems. The work described in this application will provide molecular and functional characterization of the substrate competition mechanism. The main innovation of our proposal is in synthesizing modeling, genetic, and biochemical approaches to developmental signal transduction. By combining our strengths in modeling, genetics, and biochemistry, we are uniquely positioned to formulate and experimentally test systems-level descriptions of MAPK signaling. Going beyond the early Drosophila embryo and MAPK pathway, we propose that substrate competition provides a general signal integration strategy in biomolecular networks where enzymes, such as MAPK, interact with their multiple regulators and substrates.

描述（由申请人提供）：有丝分裂激活的蛋白激酶（MAPK）信号传导途径是成人和发展组织中细胞过程的关键调节剂。放松管制的MAPK信号与多种疾病有关，这使其成为多个治疗区域的关键药物靶标。鉴于在这一重要途径中的大量组件和调节水平，如果没有定量实验，数学建模和计算分析，理解和控制其功能基本上是不可能的。早期果蝇胚胎中的末端模式系统非常适合此目的，因为其相对的解剖学简单性以及用于操纵MAPK调节剂和底物的大量遗传工具的可用性。我们已经开发了定量测定，用于对末端模式系统中MAPK磷酸化和信号传导的体内分析。基于这些分析，在我们最近发表的工作中，我们制定了一个模型，该模型Y早期胚胎中MAPK信号的空间模式由酶 - 底物竞争网络控制。具体而言，我们提出MAPK底物在彼此之间以及MAPK磷酸酶之间竞争与激活的MAPK结合。此外，我们提出，MAPK底物竞争不仅会影响MAPK途径，而且会影响其与其他信号系统的相互作用。本应用中描述的工作将提供底物竞争机制的分子和功能表征。我们建议的主要创新是合成建模，遗传和生化信号转导的生化方法。通过将我们在建模，遗传学和生物化学方面的优势结合起来，我们可以独特地定位MAPK信号传导的系统级描述。超越了早期的果蝇胚胎和MAPK途径，我们建议底物竞争在生物分子网络中提供了一般的信号整合策略，其中酶（例如MAPK）与其多个调节剂和底物相互作用。