Midgut mitochondrial function as a driver of resistance and fitness in mosquitoes

中肠线粒体功能作为蚊子抵抗力和健康的驱动因素

• 批准号: 9752692
• 负责人: Shirley Luckhart
• 金额: $ 72.64万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752692
• 关键词: Aedes; Affect; Aging; Animal Model; Anopheles Genus; Arthropods; Autophagocytosis; Behavior; Bioenergetics; Biogenesis; Biological; Biological Assay; Biology; Blood-Borne Pathogens; Caenorhabditis elegans; Cell Death; Cell Differentiation process; Cell Maintenance; Cells; Communication; Culicidae; Data; Dengue Virus; Disease; Drosophila genus; Drosophila melanogaster; Electron Transport; Engineering; Epithelial; Fat Body; Fertility; Foundations; Future; Generations; Genes; Goals; Growth Factor; Health; Human; Immunity; Infection; Insecta; Insulin; Intestines; Invertebrates; Literature; Longevity; Malaria; Mammals; Maps; Mediating; Medical; Metabolism; Microbe; Midgut; Mitochondria; Modeling; Muscle; Nematoda; Organ; Organism; Parasites; Pathogenicity; Pattern; Phenotype; Physiological; Physiological Processes; Physiology; Plasmodium falciparum; Play; Process; Production; Proteins; Quality Control; Regulation; Reproduction; Resistance; Resistance to infection; Role; Signal Transduction; Somatomedins; Stem cells; Stress; Testing; Tissues; Transgenic Organisms; Virus; Work; Zika Virus; base; brain tissue; comparative; disorder control; fitness; fly; gene product; improved; insight; life history; mitochondrial metabolism; novel; overexpression; parkin gene/protein; pathogen; prevent; trait; vector; vector mosquito

Project Summary In mosquitoes and model invertebrates, the midgut functions as a center for insulin/insulin growth factor signaling (IIS). The effects of IIS from nematodes to mammals are largely mediated through mitochondrial dynamics and activity, defined as mitochondrial biogenesis, bioenergetics, and clearance of damaged mitochondria through mitophagy. In both invertebrates and mammals, IIS-dependent mitochondrial dynamics and mitochondrial metabolism regulate a wide range of important physiologies, including epithelial barrier integrity, stem cell maintenance and differentiation, reproduction, longevity and immunity, indicating that this regulation is fundamental in living organisms. In Drosophila melanogaster and Caenorhabditis elegans, tissue- specific changes in mitochondrial function contribute to an interorgan signaling network that underlies these essential physiological processes. In particular, the fruit fly gut and nematode intestine, tissues exquisitely sensitive to stress, are intimately involved in organ-to-organ communication via local mitochondrial changes that alter systemic mitochondrial function. Given this biological conservation, our overarching goal is to broadly expand our understanding of mitochondria as master regulators of physiology in hematophagous insects of medical importance. Based on our own data and significant data from the literature and model organisms, we hypothesize that changes in the midgut mitochondria of the mosquitoes A. stephensi and A. aegypti control midgut health locally and this information is communicated systemically to control mitochondrial function and health of other tissues. Further, we hypothesize that life history trade-offs in resistance to infection, longevity and reproduction in A. stephensi and A. aegypti are fundamentally controlled locally by the midgut and coordinated systemically by mitochondrial interorgan signaling. We will test these hypotheses in three Specific Aims. In Aim 1, we will define midgut mitochondrial control of midgut health through the generation of transgenic A. stephensi and A. aegypti that overexpress gene products regulating mitochondrial biogenesis, electron transport chain protein levels and activity, mitochondrial fusion and function, and mitochondrial quality control through mitophagy. In Aim 2, we will use the transgenic mosquitoes developed in Aim 1 to define midgut mitochondrial control of systemic mitochondrial activity and fat body, flight muscle, and brain tissue health. And in Aim 3, we will use our transgenic mosquitoes to identify the networks of mitochondrial signaling that coordinately control longevity, reproduction, and resistance to pathogen infection. These phenotypes are manifested as life history trade-offs that we hypothesize are fundamentally controlled by mitochondria. By the end of these studies, we will understand how midgut mitochondrial function affects local midgut health and controls interorgan signaling to regulate and coordinate life history traits critical to vectorial capacity.

项目摘要 在蚊子和模式无脊椎动物中，中肠作为胰岛素/胰岛素生长因子的中心发挥作用。 信令（IIS）。IIS从线虫到哺乳动物的影响主要通过线粒体介导 动力学和活动，定义为线粒体生物发生，生物能量学和清除受损的 线粒体通过线粒体自噬。在无脊椎动物和哺乳动物中，IIS依赖的线粒体动力学 和线粒体代谢调节广泛的重要生理学，包括上皮屏障 完整性、干细胞维持和分化、生殖、寿命和免疫力，表明这 调节是生物体的根本。在果蝇和秀丽隐杆线虫中，组织- 线粒体功能的特定变化有助于器官间信号网络， 重要的生理过程。特别是果蝇的肠道和线虫的肠道， 对压力敏感，通过局部线粒体变化密切参与器官间的通讯 从而改变系统性线粒体功能。鉴于这种生物保护，我们的首要目标是广泛地 扩大我们对线粒体作为吸血昆虫生理学主要调节器的理解， 医学重要性根据我们自己的数据和来自文献和模式生物的重要数据，我们 假设蚊子A. stephensi和A.埃及伊蚊防治 中肠局部健康，并且该信息被系统地传达以控制线粒体功能， 其他组织的健康。此外，我们假设，生活史权衡抗感染，长寿， 和繁殖。stephensi和A.埃及伊蚊基本上由中肠局部控制， 通过线粒体器官间信号系统协调。我们将在三个具体的测试这些假设 目标。在目标1中，我们将定义中肠线粒体通过产生 转基因拟南芥stephensi和A.过表达调节线粒体生物发生的基因产物的埃及人， 电子传递链蛋白水平和活性、线粒体融合和功能以及线粒体质量 通过线粒体自噬控制。在目标2中，我们将使用目标1中开发的转基因蚊子来定义 中肠线粒体控制全身线粒体活性和脂肪体、飞行肌和脑组织 健康在目标3中，我们将使用我们的转基因蚊子来识别线粒体信号网络， 协调控制寿命、繁殖和抵抗病原体感染。这些表型是 表现为生活史的权衡，我们假设基本上是由线粒体控制的。由 通过这些研究，我们将了解中肠线粒体功能如何影响局部中肠健康， 控制器官间信号传导，以调节和协调对媒介能力至关重要的生活史特征。