Metabolic and dopamine pathways in energy sensing and adaptation in Drosophila

描述(由申请人提供)：营养水平的感知和营养的分配与储存对所有动物都具有基本的重要性，并深刻影响许多生活史特征，如寿命、繁殖力和抗饥性。尽管被认为控制这种分配的代谢、神经调节和动态平衡基因在动物中高度保守，并且集中在胰岛素信号通路上，但胰岛素反应的感知机制尚未得到很好的研究。这个项目结合了果蝇的基因功能和种群遗传学方法来解决这样的假设：(1)营养感知机制在动物中是保守的，(2)自然发生的能量感知基因的遗传变异提供了一种方式，通过这种方式，自然选择可以自适应地改变“能量状态”，以改变营养分配策略。目标1将使用基因表达操作来初步评估营养感知能力在选定的一组代谢和多巴胺途径基因中的分布，其中许多基因与人类生活史特征或疾病有关。对于目标1中显示阳性效应的基因座，我们将在目标2中确定基因敲除是通过基本通量控制产生直接效应，还是通过改变神经分泌细胞的感觉状态产生间接效应。这将通过细胞消融神经分泌细胞来实现。目标3将研究感兴趣基因座与已知的稳态信号通路的遗传相互作用，最显著的是胰岛素通路。如果切除神经分泌细胞可以消除基因特异性效应，那么我们预计这些效应也会在这些细胞分泌的胰岛素样多肽和脂肪运动激素部分被敲除的情况下发生重大变化，以及与神经肽受体突变的基因特异性相互作用。目的4将研究未来营养感受器基因的群体和表达差异，以确定这些基因中的哪些是果蝇基本生活史策略的选择目标，这些策略在地理上是可变的。能量信号机制是代谢生物学中的一个关键问题，对人类健康有着重要的影响。这个项目将在果蝇假说中评估被认为在哺乳动物中运行的机制，因此是保守的。通过这样做，它将有助于建立能量感知的这些一般特征，以及利用果蝇模型更好地了解人类代谢紊乱的潜力。 公共卫生相关性：在这个项目中，我们将全面调查果蝇营养感知机制与代谢动态平衡之间的关系。由于这些系统的组成部分在动物中是保守的，我们的工作中的见解，特别是关于代谢和多巴胺/5-羟色胺途径如何将营养和能量信息传递到胰岛素途径的见解，可以应用于人类生物学和疾病。我们将检查的许多基因功能与人类高度医学兴趣的表型有关，例如糖尿病和衰老，因此我们的研究有望指向以前未探索的代谢调节的基础和临床研究途径。 应用编号：1 R01 GM090094-01 首席调查员(S)：WF伊恩斯

DESCRIPTION (provided by applicant): The sensing of nutrient levels and allocation to use versus storage of nutrients have fundamental importance to all animals and profoundly affect many life history traits, such as longevity, fecundity, and starvation resistance. Although the metabolic, neuromodulatory, and homeostasis genes thought to control this allocation are highly conserved across animals and center on the insulin-signaling pathway, the sensing mechanisms of the insulin response are not well studied. This project uses a combination of gene functional and population genetic approaches in Drosophila to address the hypotheses that (1) nutrient sensing mechanisms are conserved in animals and (2) that naturally occurring genetic variation in energy sensing genes provides a way by which natural selection can adaptively alter "energy-stats" to change nutrient allocation strategies. Aim 1 will use gene expression manipulations to initially assess the distribution of nutrient sensing ability among a selected group of metabolic and dopamine pathway genes, many of which are associated with human life history traits or disorders. For those loci in Aim 1 exhibiting positive effects we will determine in Aim 2 if gene knockouts have direct effects through fundamental flux control or indirect effects through modifying sensing state in neurosecretory cells. This will be accomplished by cell ablation of the neurosecretory cells. Aim 3 will examine genetic interactions of the loci of interest with known homeostatic signaling pathways, most notably the insulin pathway. If ablation of neurosecretory cells abolishes gene-specific effects then we would also expect significant changes in these effects in the presence of partial knockout of insulin-like peptides and adipokinetic hormone, which are secreted from those cells, as well as genotype-specific interactions with mutations in the neuropeptide receptors. Aim 4 will examine the population and expression variation of prospective nutrient sensor genes to determine which of these are targets of selection on fundamental life history strategies that are geographically variable in Drosophila. Mechanisms of energy signaling are a critical question in metabolic biology with significant ramifications for human health. This project will evaluate in Drosophila hypotheses on mechanisms believed operating in mammals and therefore conserved. In doing this, it will help establish these general features of energy sensing, and the potential for use of the Drosophila model to better understand metabolic disorders in humans. PUBLIC HEALTH RELEVANCE: In this project, we will comprehensively investigate the relationships between nutrient sensing mechanisms and metabolic homeostasis in Drosophila. Because the components of these systems are conserved across animals, insights from our work, specifically on how the metabolic and dopamine/serotonin pathways relay nutritional and energy information to the insulin pathway, can be applied to human biology and disease. Many of the gene functions we will examine are linked to human phenotypes of high medical interest, such as diabetes and aging, and thus our research is expected to point toward previously unexplored avenues of basic and clinical inquiry into metabolic regulation. Application #: 1 R01 GM090094-01 Principal Investigator(s): Eanes, WF