IMAGiNE:Dissecting neuronal and systemic responses to interacting environmental stressors

想象：剖析神经元和系统对相互作用的环境压力源的反应

• 批准号: 2039226
• 负责人: Adriana San Miguel
• 金额: $ 56万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2039226&HistoricalAwards=false
• 关键词: IMAGiNE; Dissecting; neuronal; systemic; responses

Exposure to environmental chemicals can be harmful to ecosystems and organisms, including humans. One type of chemical can produce Reactive Oxygen Species (ROS), which are forms of oxygen that damage cells. Animals respond to ROS by escaping and producing molecules that degrade ROS as a defense mechanism. Laboratory experiments typically focus on analyzing animal responses to a single chemical, but realistic scenarios involve mixtures of multiple chemicals. Observed effects due to manipulating a single chemical could be heightened or silenced when mixtures of chemicals are considered. This project focuses on understanding how animals respond to mixtures of chemicals that produce ROS using nematodes as a model organism. Key questions include how different responses in the organism change with time, and whether the nervous system is important in generating such responses. Understanding whether different conditions and chemical mixtures result in different responses also is a key objective. This work will build understanding about how animals respond to environmental chemicals in realistic scenarios, which is important to understand the effects of such exposures on the health of humans and other species. This project also serves to develop several tools useful for the broader scientific community, such as tools for measuring escape responses in nematodes and the generation of defense enzymes. In addition, this project includes training of a diverse workforce in the biological sciences as it interfaces with data science and statistics. Finally, the outreach program associated with the project focuses on engaging with high school students from under-represented groups in STEM.Different types of noxious environments can drive the stress response and act through closely associated genetic pathways. Most studies focus on exposure to single stressors and measure responses from a single organismal readout. Yet, realistic environmental exposures consist of complex mixtures through long periods of time. How multiple stressors interact to drive the stress response in a time-dependent manner, and how diverse responses from different cells and tissues orchestrate the organismal response is not fully understood. A challenge to address these questions is the need to acquire responses from multiple levels of the organism, and to perform a broad range of combinatorial exposures that can probe a wide organismal stress response space. This work uses the model organism C. elegans to answer: 1. Whether oxidants and other stressors exhibit interacting effects on the stress response; and 2. Whether oxidant detection plays a role in the organismal oxidative stress response, and if so, whether neuronal and transcriptional programs operate in different contexts and time scales. This work determines whether different response modalities are elicited by different exposures, involves measurement of responses from multiple biological units (neuron signaling, transcription factor activity, and antioxidant enzyme gene expression) with tissue specificity, and includes development of data-driven models to identify functional relationships between different stress-response signals in the organism. A large focus of this work is on assessing the responses to combinations of chemical mixtures, and on studying the dynamics of the organismal responses. The project goals are achieved through integration of several complementary approaches, including microfluidics, fluorescence imaging, optogenetics, neuronal silencing, and statistical modeling.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

接触环境化学品可能对生态系统和生物体，包括人类有害。一种化学物质可以产生活性氧（ROS），这是一种破坏细胞的氧。动物通过逃避和产生降解ROS的分子作为防御机制来应对ROS。实验室实验通常侧重于分析动物对单一化学品的反应，但现实情况涉及多种化学品的混合物。当考虑到化学品的混合物时，由于操纵单一化学品而观察到的影响可能会加剧或减弱。该项目的重点是了解动物如何使用线虫作为模式生物对产生ROS的化学物质的混合物作出反应。关键问题包括生物体中的不同反应如何随时间变化，以及神经系统在产生这种反应中是否很重要。了解不同的条件和化学混合物是否会导致不同的反应也是一个关键目标。这项工作将了解动物在现实情况下如何对环境化学品作出反应，这对于了解此类暴露对人类和其他物种健康的影响至关重要。该项目还有助于开发对更广泛的科学界有用的几种工具，例如用于测量线虫逃逸反应和防御酶生成的工具。此外，该项目还包括在生物科学与数据科学和统计学相结合时培训多样化的劳动力。最后，与该项目相关的外展计划侧重于与STEM中代表性不足的高中生接触。不同类型的有害环境可以驱动压力反应，并通过密切相关的遗传途径发挥作用。大多数研究都集中在暴露于单一压力源，并从单一生物体读数中测量反应。然而，现实的环境暴露包括长期的复杂混合物。多种应激源如何相互作用以时间依赖的方式驱动应激反应，以及来自不同细胞和组织的不同反应如何协调生物体反应尚未完全了解。解决这些问题的一个挑战是需要从生物体的多个层面获得反应，并进行广泛的组合暴露，可以探测广泛的生物体应激反应空间。本工作使用模式生物C。优雅的回答：1。氧化剂和其他应激源是否对应激反应表现出相互作用; 2.氧化剂检测是否在生物体氧化应激反应中起作用，如果是，神经元和转录程序是否在不同的背景和时间尺度下运行。 这项工作确定是否不同的反应方式引起不同的曝光，涉及测量响应从多个生物单位（神经元信号传导，转录因子活性，抗氧化酶基因表达）与组织特异性，并包括数据驱动模型的开发，以确定不同的压力反应信号之间的功能关系在有机体。这项工作的一个大的重点是评估化学混合物的组合的反应，并研究生物体反应的动力学。该项目的目标是通过集成几种互补的方法来实现的，包括微流体，荧光成像，光遗传学，神经元沉默和统计建模。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Tuning parameter selection for penalized estimation via R2

• DOI: 10.1016/j.csda.2023.107729
• 发表时间: 2022-05
• 期刊: Comput. Stat. Data Anal.
• 作者: Julia Holter;Jonathan W. Stallrich