Collaborative Research: Uncovering the Role of Sirtuins in Linking Food Availability and Stress Tolerance Through Multi-Scale Signaling Networks in Mussels

合作研究：通过贻贝中的多尺度信号网络揭示 Sirtuins 在连接食物供应和应激耐受性方面的作用

• 批准号: 1557495
• 负责人: Neda Bagheri
• 金额: $ 10.76万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1557495&HistoricalAwards=false
• 关键词: Collaborative; Research; Uncovering; Role; Sirtuins

One of the major aims of biology is to explain how changes that occur at the sub-cellular level affect the function at higher levels of biological organization, such as organs or the whole organism. Specifically, how are changes in the expression of genes and proteins, and the concentration of metabolites of a cell, affecting the organ of which the cell is a part? Furthermore, when do these changes in organ function affect properties of the whole organism? Using the California mussel Mytilus californianus, we ask, when do subcellular changes in gill cells affect feeding rate or changes in muscle biochemistry affect the ability to close their shells? We aim to address these questions by collecting data from different levels of biological organization simultaneously, from the subcellular to the organ and organism levels in response to relevant environmental stressors, such as food availability, heat stress and the inhibition of signaling pathways. The investigators' expertise in comparative environmental physiology and computational mathematics will enable them to address the relevance of subcellular changes to predict organ and organism level changes using a mathematical model. The proposal has a strong training component and is centered on lowering the barriers to molecular and computational technologies and building a diverse community of young scientists in integrative organismal biology. Furthermore, K-12 resources will be developed on the physiological impacts of future environmental change that align with Common Core and Next Generation Science Standards.The specific objective of this study is to develop quantitative, predictive models that uncover the underlying interactions/regulations among subcellular networks (transcriptomic, metabolomic and proteomic or TMP) and their effect at the phenotypes of the organ and organism in response to environmentally relevant stressors (i.e., low/high food availability and low/high body temperature), based on high-throughput experimental data, in the intertidal mussel Mytilus californianus. The experimental design will also focus on testing a possible mechanistic link between food availability and stress tolerance by inhibiting signaling pathways involving sirtuins, which are deacylases that respond to caloric restriction and stress. This proposal distinguishes itself from previous studies on the thermal physiology of intertidal organisms in that it incorporates statistical models (including regression and decision trees) to uncover the regulatory structure of the TMP networks and determine whether the resulting topology accurately predicts observed phenotypic responses measured at the organ and whole organism levels. The PIs' complementary expertise in TMP analyses, integrative biology and computational modeling will enable them to combine "omics" technologies, organismal physiology and computational approaches to advance integrative organismal biology. The PIs are planning to disseminate the modeling framework through a research coordination network (RCN) on Integrative Organismal Biology. The results will improve our ability to predict how mussels will respond to future environmental change and thereby improve our understanding of the role of mussel aquaculture in providing a secure and sustainable food resource in the future.

生物学的主要目的之一是解释发生在亚细胞水平的变化如何影响更高水平的生物组织，如器官或整个生物体的功能。具体来说，基因和蛋白质表达的变化，以及细胞代谢产物的浓度，如何影响细胞所属的器官？ 此外，这些器官功能的变化何时影响整个有机体的特性？ 使用加州贻贝加州贻贝，我们问，什么时候鳃细胞的亚细胞变化影响摄食率或肌肉生物化学的变化影响关闭他们的壳的能力？我们的目标是解决这些问题，同时收集数据从不同层次的生物组织，从亚细胞到器官和生物体水平响应相关的环境压力，如食物的可用性，热应激和信号通路的抑制。研究人员在比较环境生理学和计算数学方面的专业知识将使他们能够解决亚细胞变化的相关性，从而使用数学模型预测器官和生物体水平的变化。该提案有一个强大的培训组成部分，并集中在降低分子和计算技术的障碍，并建立一个多元化的社区的年轻科学家在综合有机生物学。此外，K-12资源将根据共同核心和下一代科学标准开发未来环境变化的生理影响。本研究的具体目标是开发定量预测模型，揭示亚细胞网络之间的潜在相互作用/调节（转录组学、代谢组学和蛋白质组学或TMP）及其对器官和生物体响应环境相关应激物的表型的影响（即，低/高食物可用性和低/高体温），基于高通量实验数据，在潮间带贻贝加州贻贝。实验设计还将侧重于通过抑制涉及sirtuins的信号通路来测试食物可用性和应激耐受性之间可能的机制联系，sirtuins是对热量限制和应激做出反应的脱酰基酶。该建议区别于以往的研究，潮间带生物的热生理学，它采用了统计模型（包括回归和决策树），以揭示TMP网络的监管结构，并确定所得到的拓扑结构是否准确预测观察到的表型反应测量在器官和整个生物体水平。PI在TMP分析，整合生物学和计算建模方面的互补专业知识将使他们能够将联合收割机“组学”技术，生物生理学和计算方法结合起来，以推进整合生物学。PI计划通过综合有机生物学研究协调网络（RCN）传播建模框架。这些结果将提高我们预测贻贝将如何应对未来环境变化的能力，从而提高我们对贻贝水产养殖在未来提供安全和可持续食物资源方面的作用的理解。