Non-Autonomous control of aging in Drosophila

果蝇衰老的非自主控制

• 批准号: 10177832
• 负责人: BLANKA ROGINA
• 金额: $ 41万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177832
• 关键词: Affect; Age; Aging; Biogenesis; Cell membrane; Cell physiology; Cells; Citrates; Data; Deterioration; Development; Disease; Down-Regulation; Drosophila genus; Energy Metabolism; Evaluation; Fat Body; Female; Fertility; Foundations; Genes; Genetic Transcription; Glucose; Glycolysis; Goals; Health; Health Benefit; Homeostasis; Human; Insulin; Intestines; Knowledge; Lead; Life; Link; Lipids; Longevity; Longevity Pathway; Mediating; Metabolic; Metabolism; Midgut; Mitochondria; Modeling; Molecular; Mus; Nutritional; Organism; Outcome; Physiological; Production; Rattus; Regulation; Research; Resistance; Role; Science; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Tissue Model; Tissue Preservation; Tissues; Translating; Work; age related; base; citrate carrier; fly; functional decline; healthspan; insight; insulin sensitivity; insulin-like signaling; metabolic abnormality assessment; metabolomics; nonhuman primate; novel therapeutics; oxidative damage; preservation; prevent; stem cell homeostasis; stem cell proliferation; stem cells; transcriptome; transcriptome sequencing; transcriptomics

Project Summary: Aging is associated with functional decline in metabolic, physiological, proliferative, and tissue homeostasis leading to deterioration on the organismal level. The identification of therapeutic strategies that prevent or postpone age-related decline has become an urgent goal of biomedical science research. A key issue is the identification of tissue(s) that can drive organismal ageing. We will test a model of tissue-specific metabolic, physiological and molecular changes that drive organismal aging non-autonomously. Indy (I'm not dead yet) encodes a plasma membrane citrate transporter predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes (fly liver). We have shown that organism-wide reduction in Indy activity extends fly health and longevity by altering energy metabolism. Indy flies have decreased lipid and glucose levels, increased insulin sensitivity, increased mitochondrial biogenesis and reduced oxidative damage, among other effects. Additionally, we have shown that down-regulation of Indy expression preserves intestinal stem cell homeostasis, suggesting an important link between metabolic changes in the midgut, physiological homeostasis and organismal aging. Moreover, we have obtained preliminary data that specific Indy reduction in fly midgut mimics many beneficial effects of Indy reduction found in whole body Indy hypomorphs including longer lifespan. Therefore, our working hypothesis is that INDY reduction in the midgut regulates citrate levels leading to metabolic changes that preserve tissue homeostasis and slows aging non- autonomously. We propose the following specific aims. Confirm that the midgut has a key role in longevity regulation by comparing the effects on fly health and lifespan when INDY is reduced solely in the midgut, the fat body, or the oenocytes (Aim 1). Determine effects and mechanism of Indy reduction by using an integrated approach involving study of metabolism, and determination of the transcriptomic and targeted metabolomics profile in Indy flies (Aim 2). Determine the physiological mechanism by which Indy reduction in the midgut slows aging on organismal level (Aim 3). Our proposed study will advance our basic knowledge on the molecular and physiological mechanisms underlying non-autonomous effects on organismal aging. Reducing INDY homologs in worms, mice, rats and non-human primates leads to similar metabolic outcome, suggesting that our findings could be translated to mammalian organisms.

项目摘要： 衰老与代谢，生理，增殖和组织的功能下降有关 稳态导致生物水平恶化。识别治疗策略 预防或推迟与年龄有关的下降已成为生物医学科学研究的紧迫目标。钥匙 问题是可以鉴定可以驱动有机衰老的组织。我们将测试组织特异性的模型 代谢，生理和分子变化，使有机体衰老非自主。 Indy（我还没有死）编码柠檬酸质膜转运蛋白主要表达 代谢组织：中肠，脂肪体和oene核细胞（蝇肝）。我们已经证明了范围范围的减少 在Indy活动中，通过改变能量代谢，可以扩展健康和寿命。印地苍蝇降低了脂质 和葡萄糖水平，胰岛素敏感性提高，线粒体生物发生增加和氧化降低 损坏等。此外，我们已经表明Indy表达保留的下调 肠道干细胞体内平衡，表明中肠的代谢变化之间存在重要联系， 生理稳态和生物衰老。此外，我们获得了特定的初步数据 蝇中肠模仿的蝇质减少在全身Indy中发现的Indy降低的许多有益影响 包括寿命更长的低形态。因此，我们的工作假设是Midgut的Indy减少 调节柠檬酸盐的水平，导致代谢变化，以保留组织稳态并减慢非衰老 自主。我们提出以下特定目标。确认中心在寿命中具有关键作用 通过比较仅在中肠病中降低印地时对苍蝇健康和寿命的影响， 脂肪的身体或小核细胞（AIM 1）。通过使用集成的 涉及研究代谢的方法，并确定转录组和靶向代谢组学 Indy Flies的轮廓（AIM 2）。确定中肠减少Indy的生理机制 减慢生物水平的衰老（目标3）。我们提出的研究将提高我们对 对生物衰老的非自主作用的分子和生理机制。减少 蠕虫，小鼠，大鼠和非人类灵长类动物中的Indy同源物会导致类似的代谢结果，表明 我们的发现可以转化为哺乳动物生物。