Midgut mitochondria as the key to fit, Plasmodium-resistant Anopheline mosquitoes

中肠线粒体是抵抗疟原虫按蚊的关键

基本信息

批准号：
9464889
负责人：
CECILIA GIULIVI
金额：
$ 51.54万
依托单位：
UNIVERSITY OF IDAHO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-19 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9464889
关键词：
Midgut mitochondria key fit Plasmodium

项目摘要

DESCRIPTION (provided by applicant): The use of transgenic mosquitoes in an integrated malaria control strategy will require mosquitoes that completely block parasite development, yet remain competitive with wild mosquito populations. Manipulation of key signaling cascades regulating both immunity and fitness represents a novel approach to achieving this goal. In mosquitoes and other model invertebrates, the midgut functions as a center for insulin/insulin growth factor signaling (IIS), which controls immunity, lifespan, metabolism, and reproduction. The effects of midgut IIS are largely mediated through mitochondrial dynamics and activity, defined as mitochondrial biogenesis, bioenergetics, and clearance of damaged mitochondria through mitophagy. In 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, lifespan and immunity, indicating tha this regulation is fundamental in living organisms. Through our work with Anopheles stephensi, we discovered that manipulation of IIS in the midgut alters the critical balance of mitochondrial dynamics and activity, resulting in phenotypic changes in mosquito resistance to Plasmodium falciparum infection as well as to mosquito lifespan and reproduction. Thus, we propose that IIS-dependent mitochondrial dynamics and activity control "midgut health" in A. stephensi, which underlies the effects of IIS on immunity, lifespan, metabolism, and reproduction. To define how IIS-dependent mitochondrial function regulates these important phenotypes, we will use five distinct treatments - Akt overexpression (increased IIS), PTEN overexpression (decreased IIS), provisioning with human insulin or IGF1, and manipulation of endogenous A. stephensi insulin-like peptides (AsILPs) - to "push and pull" mitochondrial dynamics and activity in the midgut. Specifically, we will define how midgut IIS-dependent mitochondrial biogenesis, bioenergetics, oxidative phosphorylation, and mitophagy regulate stem cell maintenance and differentiation, epithelial integrity, and cell death processes to control fitness and Plasmodium resistance. From these studies, we will identify and manipulate specific gene targets that directly regulate mitochondrial function to retain parasite resistance while concurrently enhancing mosquito fitness. We will overexpress four of these candidate genes based on our observations and published studies and two candidate genes identified from Aims 1 and 2 in the midgut singly or in pairs. Our goal for this project is to generate highly fit, P. falciparum resistant A. stephensi that can be deployed for malaria control. In the longer term, this transgenic platform could also be additive with other gene drivers and "customized" with anti-parasite effectors for sustainable resistance management.

描述（由适用提供）：在综合疟疾控制策略中使用转基因蚊子将需要完全阻止寄生虫发育的蚊子，但仍与野生蚊子人群保持竞争力。操纵关键信号层流调节免疫力和健身的层层是实现这一目标的一种新颖方法。在蚊子和其他模型无脊椎动物中，中肠发挥了胰岛素/胰岛素生长因子信号传导（IIS）的中心，该中心控制免疫学，寿命，代谢和繁殖。中肠IIS的作用主要是通过线粒体动力学和活性介导的，该动力学和活性被定义为线粒体生物发生，生物能和通过线粒体损坏的线粒体的清除。在无脊椎动物和哺乳动物中，IIS依赖性的线粒体动力学和线粒体代谢调节了广泛的重要生理学，包括上皮屏障完整性，干细胞维持和分化，寿命和寿命和免疫，表明这种调节在生物组织中是基本的。通过与Anopheles Stephensi的工作，我们发现中肠中IIS的操纵改变了线粒体动力学和活性的临界平衡，从而导致蚊子对恶性疟原虫感染的蚊子抗性以及蚊子生命和重生的表型变化。这就是我们建议在A. Stephensi中依赖IIS依赖性的线粒体动力学和活性控制“ Midgut Health”，这是IIS对免疫，寿命，代谢和繁殖的影响的基础。 To define how IIS-dependent mitochondrial function regulates these important phenotypes, we will use five distinct treatments - Akt overexpression (increased IIS), PTEN overexpression (decreased IIS), provisioning with human insulin or IGF1, and manipulation of endogenous A. Stephensi insulin-like pepperides (AsILPs) - to "push and pull" mitochondrial dynamics and activity in the Midgut。具体而言，我们将定义Midgut IIS依赖性的线粒体生物发生，生物能，氧化磷酸化以及线粒体调节干细胞的维持和分化，上皮完整性以及控制适应性和质量抗性的细胞死亡过程。通过这些研究，我们将确定并操纵直接调节线粒体功能以保持寄生虫耐药性的同时增强蚊子适应性的特定基因靶标。我们将根据我们的观察结果和已发表的研究和两个从中肠或成对的AIMS 1和2鉴定的候选基因过表达这些候选基因的四个。我们的该项目的目标是产生高度健康，恶性疟原虫抗性A. Stephensi 可以部署用于疟疾控制。从长远来看，其他基因驱动因素也可能是其他基因驱动因素的额外的，并与抗寄生虫生效器“自定义”，用于可持续阻力管理。