A Drosophila Model for Genetic Studies of Metabolism

用于代谢遗传研究的果蝇模型

• 批准号: 7821583
• 负责人: CARL S. THUMMEL
• 金额: $ 34.63万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-19 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7821583
• 关键词: Address; Adipose tissue; Affect; Animal Model; Animals; Area; Biological; Biological Models; Cardiovascular Diseases; Chromosome Mapping; Data; Diabetes Mellitus; Dietary intake; Disease; Drosophila genus; Drosophila melanogaster; Embryonic Development; Equilibrium; Genes; Genetic; Genetic Models; Genetic Screening; Glucagon; Goals; Health; Homeostasis; Homologous Gene; Hormone Receptor; Human; Lead; Life; Lipase; Lipids; Lipolysis; Malignant Neoplasms; Maps; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methods; Molecular Genetics; Mus; Mutagenesis; Mutate; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Organism; Pathway interactions; Play; Population; Receptor Gene; Receptor Signaling; Regulatory Pathway; Research; Risk; Risk Factors; Role; Screening procedure; Signal Pathway; Site; Starvation; System; Translational Research; Translations; Triglycerides; Work; adipokinetic hormone; base; fly; gene discovery; human disease; improved; knockout gene; lipid metabolism; metabolic abnormality assessment; mutant; notch protein; novel; public health relevance; response; smoothened signaling pathway; tool

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (15): Translational Science and the specific Challenge Topic 15-DK-102: Develop improved animal models of NIDDK diseases. Metabolic homeostasis plays a central role in all aspects of postembryonic life, allowing animals to balance their dietary intake with the energy needs required for day-to-day survival. Conversely, misregulation of metabolism can lead to obesity and type 2 diabetes, which are critical risk factors for human disease, including cardiovascular disorders and cancer. The goal of our research is to use the fruit fly, Drosophila melanogaster, as a simple model system to define the central regulatory pathways that control metabolism and maintain energy homeostasis in all higher organisms, including humans. Our experimental approach exploits the unique strengths of Drosophila as a model system by conducting an open-ended genetic screen in the intact animal. This proposal arises from our ongoing studies of nuclear receptor signaling in Drosophila and the central role of these factors in maintaining metabolic homeostasis. Genetic studies have demonstrated that the nuclear receptor DHR96 is required to maintain appropriate triacylglycerol (TAG) levels in the animal. DHR96 mutants are viable, have low levels of TAG, and are sensitive to starvation, correlating with the misregulation of key lipid metabolic genes. We have discovered that the starvation sensitivity of DHR96 mutants can be rescued by introducing second-site mutations in genes that increase TAG levels, such as the adipose triglyceride lipase gene or the adipokinetic hormone receptor gene (which acts like glucagon to drive lipolysis). This observation provides a framework for identifying new genes that control lipid metabolism. We propose to exploit the DHR96 mutant as a sensitized genetic background for conducting open-ended genetic screens with the aim of identifying mutations that rescue its starvation sensitivity. Our preliminary data indicate that this screen should uncover a range of genes involved in many aspects of lipid metabolism, including genes which, when mutated, lead to obesity. Recently developed methods for efficient single-gene disruption by transposon mutagenesis will facilitate the screen and allow rapid gene identification. These studies provide a new basis for using Drosophila as means of extending our understanding of key lipid metabolic pathways that impact human health. Genetic screens represent one of the most powerful and important advantages of working in Drosophila, and offer a way to expand our understanding of specific biological pathways in new and unexpected directions. This approach has had a major impact on our understanding of human health through the delineation of the fundamental pathways that dictate embryonic development and the discovery of central signaling pathways, such as Notch, Wnt, and hedgehog signaling. We propose to exploit this strength of the fly toward the discovery of novel genes that impact lipid metabolism. We will focus our studies on newly identified Drosophila genes that have close homologs in mice and humans to facilitate the translation of our discoveries into vertebrate systems. Our long-term goal is to provide new candidates for mouse gene knockout studies and human disease gene mapping. In this way we hope to use the fly as a tool for gene discovery and extend these advances toward a better understanding of the causes of human metabolic disorders. PUBLIC HEALTH RELEVANCE: The dramatic rise in metabolic disorders, such as diabetes and obesity, poses a major health risk to the world population. This proposed research will use the fruit fly, Drosophila, as a simple genetic model system to define the fundamental mechanisms that control lipid metabolism, with the goal of providing new directions for understanding and treating human metabolic disorders.

描述(由申请人提供)：本申请涉及广泛的挑战领域(15)：翻译科学和特殊挑战主题15-DK-102：开发改进的NIDDK疾病动物模型。代谢平衡在胚胎后生活的各个方面都发挥着核心作用，使动物能够平衡饮食摄入量和日常生存所需的能量需求。相反，代谢调节不当会导致肥胖和2型糖尿病，这是人类疾病的关键风险因素，包括心血管疾病和癌症。我们的研究目标是使用果蝇作为一个简单的模式系统来定义控制包括人类在内的所有高等生物体的新陈代谢和维持能量动态平衡的中央调控途径。我们的实验方法利用了果蝇作为模型系统的独特优势，在完整的动物中进行了开放式遗传筛选。这一建议源于我们正在进行的果蝇核受体信号转导以及这些因子在维持代谢稳态中的中心作用的研究。遗传学研究表明，核受体DHR96是维持动物体内适当的三酰甘油(Tag)水平所必需的。DHR96突变体是有活力的，具有低水平的TAG，并且对饥饿敏感，这与关键脂代谢基因的错误调节有关。我们已经发现，DHR96突变体的饥饿敏感性可以通过在增加标签水平的基因中引入第二位点突变来挽救，例如脂肪甘油三酯脂肪酶基因或脂肪运动激素受体基因(其作用类似于胰高血糖素来驱动脂肪分解)。这一观察结果为识别控制脂代谢的新基因提供了一个框架。我们建议利用DHR96突变体作为敏化的遗传背景进行开放式遗传筛选，目的是识别挽救其饥饿敏感性的突变。我们的初步数据表明，这一筛查应该会揭示一系列涉及脂肪代谢许多方面的基因，包括当突变时导致肥胖的基因。最近开发的通过转座子突变有效地破坏单基因的方法将有助于筛选和快速鉴定基因。这些研究为利用果蝇作为扩大我们对影响人类健康的关键脂代谢途径的理解提供了新的基础。基因筛查代表了在果蝇中工作的最强大和最重要的优势之一，并提供了一种方法，以新的和意想不到的方向扩大我们对特定生物途径的理解。这种方法通过描绘决定胚胎发育的基本途径和发现中央信号途径，如Notch、Wnt和Hedgehog信号，对我们对人类健康的理解产生了重大影响。我们建议利用苍蝇的这种优势来发现影响脂肪代谢的新基因。我们将把我们的研究重点放在新发现的在老鼠和人类中具有密切同源性的果蝇基因上，以促进我们的发现转化为脊椎动物系统。我们的长期目标是为小鼠基因敲除研究和人类疾病基因定位提供新的候选基因。通过这种方式，我们希望将苍蝇作为基因发现的工具，并将这些进展扩展到更好地理解人类代谢紊乱的原因。 公共卫生相关性：糖尿病和肥胖症等代谢紊乱的急剧增加对世界人口构成了重大的健康风险。这项拟议的研究将以果蝇作为一个简单的遗传模型系统，来定义控制脂肪代谢的基本机制，目的是为理解和治疗人类代谢疾病提供新的方向。