Genetic Network Linking Immunity to Energetic Stress and Metabolism

描述(由申请人提供)： 营养因素可以对免疫防御产生深远的影响，但将饮食营养与免疫联系起来的机制尚不清楚。在拟议项目下开展的工作将从生理和遗传角度建立营养和防御之间的关系，并最终确定导致饮食引起的个体特异性免疫变化的基因。该项目将利用模式昆虫黑腹果蝇，它的代谢和免疫系统与脊椎动物的同源系统高度保守。在该项目的目标1中，将评估提供不同营养成分的饲料的黑腹金龟对细菌感染的抵抗力(以免疫系统活性和细菌增殖抑制衡量)和对感染的耐受性(以受感染时维持健康的能力衡量)。被评估的实验饮食将在蛋白质、糖和脂肪水平上有所不同。该项目的目标2将检验这一假设，即特定的免疫和代谢信号通路在感染期间是联系在一起的，因此免疫系统的激活会导致新陈代谢和能量利用的改变。在感染的早期阶段，IMD(免疫系统)、JNK(应激反应)和胰岛素样(代谢)信号通路将被基因干扰，以测试不同过程之间的交叉交流。该项目的目标3将在概念上将前两个目标联系起来，研究自然发生的变异。众所周知，自然种群中的个体在免疫相关和代谢特征上都是遗传可变的。将在目标3下进行的实验将确定抗性和耐受性表型在多大程度上由饮食的特定基因效应决定(称为基因与环境的交互作用)。这些相互作用构成了个性化医学的概念基础，理解它们将对高级临床治疗至关重要。对已知多态的分析和无偏见的全基因组关联作图将被用来识别与饮食有关的负责基因型特异性免疫改变的基因。在所有三个目标下收集的数据将为饮食对防御质量的影响提供新的和广泛的全面理解，对临床和进化生物学具有重要意义。

DESCRIPTION (provided by applicant): Nutritional factors can have profound influence on immune defense, but the mechanisms linking dietary nutrition to immunity are poorly understood. Work performed under the proposed project will establish the relationship between nutrition and defense from physiological and genetic perspectives, and will ultimately identify genes contributing to individual-specific alteration in immunity due to diet. The project will make use of the model insect Drosophila melanogaster, which has metabolic and immune systems that are highly conserved with homologous systems in vertebrates. In Aim 1 of the project, D. melanogaster provided with diets of varying nutritional composition will be evaluated for resistance to bacterial infection (measured as immune system activity and suppression of bacterial proliferation) and tolerance of infection (measured as the ability to sustain health while infected). The experimental diets to be evaluated will vary in protein, sugar and fat levels. Aim 2 of the project will test the hypothesis that specific immune and metabolic signaling pathways are linked during infection, such that activation of the immune system causes altered metabolism and energetic utilization. The IMD (immune system), JNK (stress response), and insulin-like (metabolism) signaling pathways will be genetically disrupted to test for cross-communication between processes during the early stages of an infection. Aim 3 of the project will conceptually link the first two Aims in a study of naturally occurring variation. It is known that individuals in natural populations are genetically variable for both immune-related and metabolic traits. Experiments to be performed under Aim 3 will determine the degree to which resistance and tolerance phenotypes are determined by genotype-specific effects of diet (termed genotype-by-environment interaction). These interactions form the conceptual basis of personalized medicine, and understanding them will be crucial for advanced clinical therapeutics. Analysis of known polymorphisms and unbiased genome-wide association mapping will be employed to identify genes responsible for genotype-specific immunological alteration with diet. The data collected under all three Aims will provide novel and broadly comprehensive understanding of dietary effects on defense quality, with critical implications for clinical and evolutionary biology.