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

生物学的主要目的之一是解释在亚细胞水平上发生的变化如何影响生物组织的更高水平上的功能，例如器官或整个有机体。具体地说，基因和蛋白质的表达以及细胞代谢物浓度的变化如何影响该细胞所属的器官？此外，器官功能的这些变化何时会影响整个有机体的特性？使用加利福尼亚贻贝，我们问，什么时候鳃细胞的亚细胞变化会影响摄食率，或者肌肉生化的变化会影响关闭贝壳的能力？我们的目标是通过同时收集不同水平的生物组织的数据来解决这些问题，从亚细胞到器官和有机体水平，以响应相关的环境应激，如食物可获得性、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利用数学模型解决亚细胞变化的相关性，以预测器官和生物体水平的变化。该提案有很强的培训成分，重点是降低分子和计算技术的壁垒，并在综合生物生物学领域建立一个多样化的年轻科学家社区。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。这项研究的具体目标是开发定量的预测模型，揭示潮间带贻贝中亚细胞网络(转录组、代谢组和蛋白质组或TMP)之间的潜在相互作用/调节，以及它们对与环境相关的应激源(即低/高食物可获得性和低/高体温)的器官和有机体表型的影响。实验设计还将专注于通过抑制涉及sirtuins的信号通路来测试食物可获得性和压力耐受性之间可能的机械联系。sirtuins是一种对卡路里限制和压力做出反应的脱酰基酶。这一建议与以前关于潮间带生物热生理学的研究的不同之处在于，它纳入了统计模型(包括回归和决策树)，以揭示TMP网络的调节结构，并确定所产生的拓扑是否准确地预测了在器官和整个生物体水平上测量的观察到的表型反应。PIS在TMP分析、综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“组学”技术、生物生理学和计算方法结合起来，以推进综合生物生物学。私人投资机构正计划通过综合组织生物学研究协调网络(RCN)传播建模框架。研究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的食物资源方面的作用的理解。

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.