Insulin, IGF and Insulin Signaling: effects on Anopheles lifespan and immunity

胰岛素、IGF 和胰岛素信号传导：对按蚊寿命和免疫力的影响

• 批准号: 8278642
• 负责人: Michael Allen Riehle
• 金额: $ 50.05万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-09 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278642
• 关键词: Accounting; Affect; Africa; Aging; Animal Model; Anopheles Genus; Area; Blood; Caenorhabditis elegans; Chemicals; Competence; Culicidae; Data; Dengue Virus; Development; Drosophila melanogaster; Drug resistance; Engineering; Exhibits; Fat Body; Female; Growth Factor; Head; Hormones; Human; Immune response; Immune system; Immunity; Infection; Insulin; Insulin-Like Growth Factor I; Invertebrates; Longevity; Malaria; Mammals; Midgut; Modeling; Modification; Monitor; Mosquito-borne infectious disease; Natural Immunity; Nature; Nutrient; Organism; Ovary; Oxidative Stress; Oxidative Stress Induction; PTEN gene; Parasites; Peptides; Physiological; Physiology; Plasmodium falciparum; Play; Production; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Reproduction; Role; Signal Transduction; Testing; Time; Tissues; Transgenes; Transgenic Organisms; Variant; West Nile virus; Work; abstracting; base; feeding; insulin signaling; killings; overexpression; oxidative damage; pesticide resistance; programs; research study; senescence; transmission process; vector; vector mosquito

Abstract Increased drug and pesticide resistance has rendered many control programs for mosquito-borne diseases useless, resulting in an urgent need for new control strategies. Since malaria parasites must develop for up to two weeks in the mosquito there is opportunity to disrupt this development by enhancing mosquito innate immunity or shortening the mosquito's lifespan. The insulin/IGF-1 signaling cascade (ISC) has been shown to regulate both innate immunity and lifespan in invertebrates, and could be manipulated to reduce vector competence of mosquitoes. Based on our preliminary data, exogenous insulin and IGF-1 in the bloodmeal may also play major roles in the midgut and other tissues. To test these hypotheses, we will first determine whether exogenous human insulin and IGF-1 can stimulate the ISC in the midgut and other tissues, such as the fat body, in the mosquito Anopheles stephensi. We will also test the impact of these factors on oxidative stress and NO production, key components of aging, innate immunity, and signaling. Next we will engineer An. stephensi mosquitoes to express active forms of two ISC proteins, Akt and PTEN, in the midgut after a bloodmeal. Because AKT activates the midgut ISC and PTEN has the opposite effect, we will be able to answer three questions. 1) Does the midgut ISC regulate oxidative stress and in turn aging? 2) Does the midgut ISC affect signaling in other tissues? 3) Do changes to the ISC affect Plasmodium falciparum development? Finally, we will examine the impact of physiological levels of exogenous human insulin and IGF- 1 on the transgenic mosquitoes described above. Insulin levels in human blood can vary by as much as 10-fold after a meal and during malaria parasite infection. By understanding and taking into account the effects of this naturally occurring variation in human bloodmeals we can better predict the efficacy of Akt and PTEN overexpression on critical variables (e.g., lifespan and immunity) of vector competence. In summary, our proposed work will test both basic and applied hypotheses regarding the ISC and its impacts on mosquito physiology and vector competence that were conceptualized for Caenorhabditis elegans, Drosophila melanogaster and mammals. In addition, our work offers a different approach to the transgenic modification of mosquitoes to limit their vectorial capacity. Relevance: Many mosquito-borne disease agents, including malaria parasites, dengue virus, and West Nile virus, must develop in mosquitoes for extended periods before being transmitted to humans. We hope to enhance innate immunity and/or reduce average lifespan of a model mosquito below this development period so that transmission of malaria parasites is reduced or eliminated.

摘要 抗药性和杀虫剂抗药性的增加使得许多蚊媒疾病的控制方案 毫无用处，导致迫切需要新的控制策略。由于疟疾寄生虫必须发展到 两个星期的蚊子有机会破坏这种发展，通过提高蚊子先天 免疫力或缩短蚊子的寿命。胰岛素/IGF-1信号级联（ISC）已被证明是 调节无脊椎动物的先天免疫和寿命，并可被操纵以减少载体 蚊子的能力。根据我们的初步数据，血粉中的外源性胰岛素和IGF-1 也可能在中肠和其他组织中发挥重要作用。为了测试这些假设，我们首先确定 外源性人胰岛素和IGF-1是否可以刺激中肠和其他组织中的ISC，如 斯氏按蚊肥胖的身体。我们还将测试这些因素对氧化的影响， 压力和NO的产生，衰老的关键成分，先天免疫和信号传导。接下来，我们将设计一个。 斯氏蚊子表达活性形式的两个ISC蛋白，Akt和PTEN，在中肠后， 血粉因为AKT激活中肠ISC，而PTEN具有相反的作用，我们将能够 回答三个问题。1)中肠ISC是否调节氧化应激进而衰老？2)是否 中肠ISC影响其他组织的信号传导？3)ISC的改变会影响恶性疟原虫吗 发展？最后，我们将研究外源性人胰岛素和IGF-1的生理水平的影响。 1对上述转基因蚊子的影响。人体血液中的胰岛素水平可以变化多达10倍 在饭后和疟疾寄生虫感染期间。通过理解和考虑到这一影响， 通过分析人血粉中天然存在的变异，我们可以更好地预测Akt和PTEN的功效， 在关键变量上的过表达（例如，寿命和免疫力）。总之，我们的 拟议的工作将测试有关ISC及其对蚊子影响的基本假设和应用假设 生理学和载体的能力，概念化的秀丽隐杆线虫，果蝇 黑腹动物和哺乳动物此外，我们的工作提供了一种不同的方法来转基因修饰的， 蚊子来限制它们的传病能力。相关性：许多蚊媒疾病病原体，包括疟疾寄生虫、登革热 病毒和西尼罗河病毒必须在蚊子中发展很长一段时间， 传染给人类我们希望增强先天免疫力和/或减少 模型蚊子的平均寿命低于该发育期， 减少或消除疟疾寄生虫的传播。

项目成果

The effects of ingested mammalian blood factors on vector arthropod immunity and physiology.

• DOI: 10.1016/j.micinf.2013.01.003
• 发表时间: 2013-03
• 期刊: Microbes and infection
• 影响因子: 5.8
• 作者: Pakpour N;Akman-Anderson L;Vodovotz Y;Luckhart S
• 通讯作者: Luckhart S

Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi.

• DOI: 10.1016/j.dci.2015.06.012
• 发表时间: 2015-11
• 期刊: Developmental and comparative immunology
• 影响因子: 2.9
• 作者: Pietri JE;Pietri EJ;Potts R;Riehle MA;Luckhart S
• 通讯作者: Luckhart S

Knockdown of mitogen-activated protein kinase (MAPK) signalling in the midgut of Anopheles stephensi mosquitoes using antisense morpholinos.

• DOI: 10.1111/imb.12103
• 发表时间: 2014-10
• 期刊: Insect molecular biology
• 影响因子: 2.6
• 作者: Pietri JE;Cheung KW;Luckhart S
• 通讯作者: Luckhart S

Mitochondrial NAD+-dependent malic enzyme from Anopheles stephensi: a possible novel target for malaria mosquito control.

• DOI: 10.1186/1475-2875-10-318
• 发表时间: 2011-10-26
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Pon J;Napoli E;Luckhart S;Giulivi C
• 通讯作者: Giulivi C

Two insulin-like peptides differentially regulate malaria parasite infection in the mosquito through effects on intermediary metabolism.

两种胰岛素样肽通过影响中间代谢来差异调节蚊子中的疟疾寄生虫感染。

• DOI: 10.1042/bcj20160271
• 发表时间: 2016
• 期刊: The Biochemical journal
• 作者: Pietri,JoseE;Pakpour,Nazzy;Napoli,Eleonora;Song,Gyu;Pietri,Eduardo;Potts,Rashaun;Cheung,KongW;Walker,Gregory;Riehle,MichaelA;Starcevich,Hannah;Giulivi,Cecilia;Lewis,EdwinE;Luckhart,Shirley
• 通讯作者: Luckhart,Shirley