Collaborative Research: RUI: 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，以及细胞代谢物的浓度，是如何影响细胞所属器官的？此外，这些器官功能的变化何时会影响整个生物体的特性？利用加利福尼亚贻贝，我们问，鳃细胞的亚细胞变化何时影响摄食率或肌肉生物化学变化何时影响合壳能力？我们的目标是通过同时收集来自不同水平的生物组织的数据来解决这些问题，从亚细胞到器官和生物体水平，以响应相关的环境应激源，如食物供应，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。该提案具有很强的培训成分，其核心是降低分子和计算技术的门槛，并建立一个多元化的综合生物生物学年轻科学家社区。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。本研究的具体目标是基于潮间带贻贝（Mytilus californianus）的高通量实验数据，开发定量预测模型，揭示亚细胞网络（转录组学、代谢组学和蛋白质组学或TMP）之间潜在的相互作用/调节及其对器官和生物体表型的影响，以响应环境相关的压力源（即低/高食物可用性和低/高体温）。实验设计还将侧重于通过抑制sirtuins（一种对热量限制和压力做出反应的去乙酰化酶）的信号通路，来测试食物供应和压力耐受性之间可能的机制联系。该研究与以往潮间带生物热生理研究的不同之处在于，它采用了统计模型（包括回归和决策树）来揭示TMP网络的调控结构，并确定所得到的拓扑结构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。pi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结合“组学”技术，生物生理学和计算方法来推进综合生物生物学。pi正计划通过综合生物研究协调网络（RCN）传播建模框架。这些结果将提高我们预测贻贝如何应对未来环境变化的能力，从而提高我们对贻贝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。

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.