Metabolic and dopamine pathways in energy sensing and adaptation in Drosophila

果蝇能量感知和适应的代谢和多巴胺途径

• 批准号: 7770343
• 负责人: Walter F. EANES
• 金额: $ 30.09万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770343
• 关键词: Ablation; Address; Affect; Aging; Alleles; Animals; Base Sequence; Biology; Body Size; Candidate Disease Gene; Cells; Clinical; Code; DNA Sequence; Diabetes Mellitus; Disease; Dopamine; Drosophila genus; Enzymes; Evolution; Exhibits; Female; Fertility; Gene Combinations; Gene Expression; Gene-Modified; Genes; Genetic; Genetic Variation; Genotype; Health; Homeostasis; Human; Human Biology; Insulin; Insulin Signaling Pathway; Knock-out; Link; Longevity; Maintenance; Mammals; Medical; Metabolic; Metabolic Diseases; Modeling; Molecular Genetics; Mutation; Natural Selections; Neuromodulator; Neuropeptide Receptor; North America; Nutrient; Nutritional; Organism; Pathway interactions; Pattern; Peptides; Phenotype; Population; Population Genetics; Principal Investigator; Proteins; RNA Interference; Regulation; Research; Resistance; Schedule; Serotonin; Signal Pathway; Signal Transduction; Starvation; System; Transcript; Variant; Work; adipokinetic hormone; base; detection of nutrient; gene function; insight; interest; knockout gene; life history; overexpression; prospective; public health relevance; receptor; response; sensor; trait

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

描述（由申请人提供）：营养水平的感知和营养的使用与储存分配对所有动物都具有根本的重要性，并深刻影响许多生活史特征，如寿命、繁殖力和耐饥饿性。尽管被认为控制这种分配的代谢、神经调节和稳态基因在动物中高度保守，并且集中在胰岛素信号传导途径上，但胰岛素反应的传感机制尚未得到很好的研究。该项目在果蝇中使用基因功能和群体遗传学方法的组合来解决以下假设：（1）营养感应机制在动物中是保守的;（2）能量感应基因中自然发生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，初步评估营养感知能力的分布在一组选定的代谢和多巴胺途径基因，其中许多与人类生活史特征或疾病。对于目标1中表现出积极作用的那些位点，我们将在目标2中确定基因敲除是否通过基本通量控制具有直接作用或通过改变神经分泌细胞中的传感状态具有间接作用。这将通过神经分泌细胞的细胞消融来完成。目标3将检查感兴趣的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。如果神经分泌细胞的消融消除了基因特异性效应，那么我们也可以预期，在胰岛素样肽和脂肪运动激素（从这些细胞分泌）部分敲除的情况下，这些效应会发生显著变化，以及与神经肽受体突变的基因型特异性相互作用。目的4将研究人口和表达变化的前瞻性营养传感器基因，以确定这些是选择的基本生活史策略，在果蝇的地理变量的目标。能量信号传导机制是代谢生物学中的一个关键问题，对人类健康具有重大影响。这个项目将在果蝇中评估被认为在哺乳动物中起作用的机制的假设，因此是保守的。在这样做的过程中，它将有助于建立能量感知的这些一般特征，以及使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：在本计画中，我们将全面探讨果蝇的营养感应机制与代谢平衡之间的关系。由于这些系统的组成部分在动物中是保守的，因此我们的工作，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给胰岛素途径的见解，可以应用于人类生物学和疾病。我们将研究的许多基因功能与具有高度医学意义的人类表型有关，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基础和临床研究途径。 申请编号：1 R 01 GM 090094 -01 主要研究者：Eanes，WF