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: 7524385
• 负责人: Michael Allen Riehle
• 金额: $ 51.17万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524385
• 关键词: Affect; Africa South of the Sahara; Age; Aging; Animal Model; Anopheles Genus; Anopheles gambiae; Area; Blood; Brain; Caenorhabditis elegans; Chemicals; Competence; Condition; Culicidae; Data; Development; Drosophila melanogaster; Engineering; Exhibits; Fat Body; Female; Goals; Growth Factor; Hormones; Human; Immune response; Immune system; Immunity; India; Infection; Insulin; Insulin-Like Growth Factor I; Invertebrates; Life; Longevity; Malaria; Mammals; Middle East; Midgut; Modeling; Modification; Monitor; Mosquito-borne infectious disease; Natural Immunity; Nematoda; Nutrient; Organism; Ovary; Oxidative Stress; Oxidative Stress Induction; PTEN gene; Parasites; Peptides; Pharmaceutical Preparations; Physiological; Physiology; Plasmodium; Plasmodium falciparum; Production; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Publishing; Reproduction; Signal Transduction; Southeastern Asia; Testing; Time; Tissues; Transgenes; Transgenic Organisms; Variant; Virus; Week; Work; base; biological adaptation to stress; day; feeding; insulin signaling; killings; pathogen; pesticide resistance; prevent; programs; research study; senescence; transmission process; vector; vector mosquito

DESCRIPTION (provided by applicant): Increased drug and pesticide resistance has rendered many control programs for mosquito-borne diseases useless, resulting in an urgent need for new control strategies. Malaria parasites must develop for up to two weeks in the mosquito, and conceptually, this development can be disrupted by enhancing mosquito innate immunity or by shortening the mosquito's lifespan. The insulin/IGF-1 signaling cascade (ISC) regulates both innate immunity and lifespan in Caenorhabditis elegans and Drosophila melanogaster, and, thus, could be manipulated to reduce vector competence of mosquitoes. Based on our preliminary data, exogenous insulin in the bloodmeal modulates not only lifespan and oxidative stress response in female mosquitoes, but also Plasmodium development. To further elucidate these promising results, 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 and innate immunity in An. stephensi? (2) Does the midgut ISC affect signaling in other An. stephensi tissues? And (3) How do changes to the ISC affect Plasmodium falciparum development in An. stephensi? 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 the effects of this naturally occurring variation in human bloodmeals, we can better predict the efficacy of Akt and PTEN over expression 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 model invertebrates and mammals. In addition, our work offers a different approach to the transgenic modification of mosquitoes to limit their vectorial capacity. PUBLIC HEALTH RELEVANCE After being ingested in a bloodmeal, malaria parasites, viruses, and nematodes must develop in mosquitoes for extended periods before being transmitted to humans and reservoir hosts. Our goal is to enhance innate immunity or reduce the lifespan of a model mosquito to prevent completion of pathogen development, so that transmission is reduced or eliminated.

描述（由申请人提供）：蚊虫对药物和杀虫剂的抗药性增加，使得许多蚊媒疾病的控制方案无效，因此迫切需要新的控制策略。疟疾寄生虫必须在蚊子体内发育长达两周，从概念上讲，这种发育可以通过增强蚊子的先天免疫或缩短蚊子的寿命来中断。胰岛素/IGF-1信号级联（ISC）调节秀丽隐杆线虫（Caenorhabditis elegans）和黑ogaster果蝇（Drosophila melanogaster）的先天免疫和寿命，因此可以通过操纵来降低蚊子的媒介能力。根据我们的初步数据，血液中的外源性胰岛素不仅可以调节雌蚊的寿命和氧化应激反应，还可以调节疟原虫的发育。为了进一步阐明这些有希望的结果，我们将首先确定外源性人胰岛素和IGF-1是否可以刺激斯氏按蚊中肠和其他组织（如脂肪体）的ISC。我们还将测试这些因素对氧化应激和一氧化氮生成、衰老关键成分、先天免疫和信号传导的影响。接下来我们将设计An。在吸血后的中肠中表达两种ISC蛋白Akt和PTEN的活性形式。由于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，进而调节衰老和先天免疫？stephensi吗?(2)中肠ISC是否影响其他An的信号转导？stephensi组织?(3) ISC的改变如何影响恶性疟原虫在中国的发展。stephensi吗?最后，我们将研究外源性人胰岛素和IGF-1生理水平对上述转基因蚊子的影响。在餐后和疟疾寄生虫感染期间，人体血液中的胰岛素水平可以变化多达10倍。通过了解这种在人类血液中自然发生的变异的影响，我们可以更好地预测Akt和PTEN过表达对载体能力关键变量（如寿命和免疫力）的影响。总之，我们提出的工作将测试关于ISC及其对模型无脊椎动物和哺乳动物的蚊子生理和媒介能力的影响的基本和应用假设。此外，我们的工作提供了一种对蚊子进行转基因改造以限制其媒介能力的不同方法。疟疾寄生虫、病毒和线虫经人血摄入后，必须在蚊子体内发育较长时间，然后才能传播给人类和宿主。我们的目标是增强先天免疫或缩短模式蚊子的寿命，以防止病原体发育完成，从而减少或消除传播。