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.

这项研究检验了这样一个假设：能量代谢效率低下的个体抵抗感染的能力会下降，进而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精力。这些反应会耗尽原本用于生长、维持和繁殖的能量供应，特别是在能量有限的情况下。当无法获得营养物质或当其基因不允许将营养物质有效加工成能量供应时，个体生物体的能量可能会受到限制。该研究还将解决有关对抗感染如何改变新陈代谢率的问题。通过使用具有与人类相似的自然免疫反应的模型遗传生物——果蝇，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抵抗感染的能力的关键信息。这项研究还将用于为入门生物学实验室设计新的练习，帮助学生综合入门生物学课程涵盖的不同主题的信息，从进化到免疫和生理学。该项目测试了激活免疫系统所需能量的预测在发育过程中，能量代谢效率低下的个体抵抗感染的能力会降低，从而导致未来成年繁殖能力的下降。该项目在经过充分研究的遗传系统中，在有机体、分子和生理水平上将先天免疫和能量代谢途径之间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型，其中一种基因型的线粒体-核相互作用被破坏，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天然病原体雷氏普罗威登斯菌感染后是否具有较低的感染存活率和对生殖健康的更大有害后果。实验还将修改营养饮食，以进一步减少所有基因型中可用于免疫反应的能量。目标 2 将测量潜在分子途径的激活和细胞能量代谢的各个方面，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、测量能量传感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有机体代谢率的指标。