DISSERTATION RESEARCH: Energetic mechanisms underlying fitness consequences of immune responses

论文研究：免疫反应适应性后果背后的能量机制

• 批准号: 1701876
• 负责人: Kristi Montooth
• 金额: $ 1.99万
• 依托单位: University of Nebraska-Lincoln
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1701876&HistoricalAwards=false
• 关键词: DISSERTATION; RESEARCH; Energetic; mechanisms; underlying

This research tests the hypothesis that individuals with inefficient energy metabolism will have a decreased ability to fight infection, which in turn will decrease their future reproductive ability. Fighting infection requires individuals to invest energy in immune responses. These responses can deplete energy supplies that would otherwise be used for growth, maintenance, and reproduction, particularly when energy is limited. Individual organisms may be energy limited when nutrients are not available or when their genes do not allow efficient processing of nutrients into energy supplies. The research will also address questions about how fighting infection changes metabolic rate. By using the model genetic organism, Drosophila melanogaster, which has natural immune responses that are similar to humans, this project will generate critical information on how genetic variation in energy metabolism affects the ability of human cells to fight infection. This research will also be used to design new exercises for introductory biology laboratories that will help students synthesize information across diverse topics covered in introductory biology courses, from evolution to immunity and physiology.This project tests the prediction that the energy required to activate the immune system during development decreases the ability of individuals with inefficient energy metabolism to fight infection, and creating a resulting decrease in future adult reproduction. The project connects the effects of interactions between innate immunity and energy metabolism pathways at the organismal, molecular, and physiological levels in a well-studied genetic system. The experiments take advantage of a well-characterized set of genotypes, one of which has a disrupted mitochondrial-nuclear interaction that results in inefficient energy metabolism. Objective 1 will quantify whether flies with inefficient energy metabolism have lower infection survival and greater deleterious consequences for reproductive fitness after infection by a natural pathogen, Providencia rettgeri. Experiments will also modify the nutrient diet to further decrease the energy available for immune responses in all genotypes. Objective 2 will measure the activation of underlying molecular pathways and aspects of cellular energy metabolism to explain effects on tradeoffs between immunity and reproduction. Experiments include quantifying levels of antimicrobial peptide induction, measuring the amounts of key proteins in energy-sensing pathways, assessing the bacterial load during infection, and monitoring indicators of the cellular energetic state and organismal metabolic rate during infection.

这项研究验证了一种假设，即能量代谢低效的个体对抗感染的能力会降低，这反过来又会降低他们未来的生殖能力。对抗感染需要个人在免疫反应上投入能量。这些反应可能会耗尽原本用于生长、维持和繁殖的能源供应，特别是在能源有限的情况下。当营养物质不可用时，或者当它们的基因不允许将营养物质有效地加工成能量供应时，个别生物体可能能量有限。这项研究还将解决有关抗击感染如何改变代谢率的问题。通过使用模式遗传有机体黑腹果蝇，它具有与人类相似的自然免疫反应，该项目将产生关于能量代谢的遗传变异如何影响人类细胞抗击感染能力的关键信息。这项研究还将用于为生物入门实验室设计新的练习，帮助学生综合生物入门课程中涵盖的从进化到免疫和生理学等不同主题的信息。该项目测试了一种预测，即在发育过程中激活免疫系统所需的能量会降低能量代谢效率低下的个体对抗感染的能力，从而导致未来成年生殖的减少。该项目在一个经过充分研究的遗传系统中，在生物、分子和生理水平上将先天免疫和能量代谢途径之间的相互作用的影响联系起来。这些实验利用了一组特征明确的基因类型，其中一种基因类型的线粒体-核相互作用中断，导致能量代谢效率低下。目标1将量化能量代谢效率低下的果蝇在被自然病原体普罗维登西亚雷特吉里(Providencia Rettgeri)感染后，是否具有较低的感染存活率和更大的生殖适合性有害后果。实验还将修改营养饮食，以进一步减少所有基因型可用于免疫反应的能量。目标2将测量潜在的分子途径和细胞能量代谢方面的激活，以解释对免疫和生殖之间权衡的影响。实验包括量化抗菌肽诱导水平，测量能量感应途径中关键蛋白质的数量，评估感染期间的细菌负荷，以及监测感染期间细胞能量状态和机体代谢率的指标。