The mechanisms of serotonin-based signaling in food perception and DR-mediated longevity

基于血清素的信号传导在食物感知和 DR 介导的长寿中的机制

• 批准号: 9610851
• 负责人: Hillary Ann Miller
• 金额: $ 3.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2021-03-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9610851
• 关键词: Address; Adenylate Cyclase; Aging; Aging-Related Process; Animal Model; Animals; Biological; Biomedical Research; CD2 Antigens; Caenorhabditis elegans; Cells; Cellular Structures; Clinical; Data; Disease; Drug Antagonism; Energy Intake; Environment; Event; Exposure to; FMO2; Food; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Transcription; Goals; Health; Heat-Shock Response; Human; Image; Individual; Insulin; Intervention; Intestines; Knock-out; Knowledge; Link; Longevity; Longevity Pathway; Mammals; Maps; Measures; Mediating; Metabolic; Methodology; Methods; Modeling; Modernization; Modification; Monitor; Nematoda; Nervous system structure; Neurons; Neuropeptides; Neurotransmitters; Nutrient; Organism; Oxygen; Pathway interactions; Peptide Signal Sequences; Perception; Peripheral; Play; Proteins; Proxy; Publications; Publishing; RNA interference screen; Reporter; Reporting; Research; Research Personnel; Resistance; Role; Satiation; Sensory; Serotonin; Serotonin Antagonists; Serotonin Production; Signal Pathway; Signal Transduction; Signaling Molecule; Smell Perception; Starvation; Stimulus; Stress; Synapses; Techniques; Testing; Therapeutic; Tissues; Work; age related; base; biological adaptation to stress; demographics; dietary restriction; experimental study; genetic manipulation; healthspan; high throughput screening; human old age (65+); improved; insight; neural circuit; neurotransmission; novel; prevent; receptor; reconstruction; response; screening

Project Summary. It is estimated that by 2050 the number of US citizens over the age of 65 will reach nearly 100 million, more than twice as many as today. As the demographics of the modern world continue to skew older, understanding and mitigating the aging process has become increasingly important within biomedical research. Aging researchers have made many discoveries in the past 25 years and have demonstrated that slowing aging can prevent or delay the formation of many diseases and improve overall health. Many of these conserved “longevity pathways” were initially discovered using the nematode Caenorhabditis elegans, where easy genetic manipulation and brief lifespans benefit aging research. A number of these highly regarded publications have identified multiple genetic pathways that link the perception of stress by the nervous system with distinct signaling networks and downstream effectors that improve health and longevity. While these studies provide substantial evidence that cell to cell signaling regulates aging and is common to multiple longevity pathways, they lack the specific signals, receptors, neural circuits, and downstream effectors involved. Some of these studies have reported the important neurotransmitter serotonin as a necessary signaling molecule upstream of the metabolic changes that occur in peripheral tissues, which corroborates the preliminary data I will present in this proposal. More specifically, our data show that the most well-studied longevity intervention, dietary restriction (DR), acts in part through a cell non-autonomous signaling pathway that is inhibited by the smell of food in C. elegans. We further find that DR leads to induction of an intestinal gene, flavin-containing monooxygenase-2 (fmo-2), that is both necessary and sufficient to improve healthspan, stress resistance, and longevity. We also observe that induction of fmo-2 and extension of lifespan both depend on the serotonergic signaling and can be recapitulated by the serotonin antagonist drug, mianserin. This project will elucidate components of the cell non-autonomous pathway initiated by the lack of food that eventually leads to intestinal fmo-2 induction and extension of lifespan. To that end I will identify the serotonergic neuron which initiates the signaling cascade (Aim 1), and determine which neuron receives that signal (Aim 2). From here, I will discover the signaling events that occur downstream of serotonin release (or absence) using a number of screening methods (Aim 3). Collectively, these aims will enhance our understandings of a highly conserved signaling pathway that modifies aging. The ultimate goal of my research is to exploit the biological insights gained here to develop therapeutics that increase human healthspan.

项目摘要。 据估计，到2050年，65岁以上的美国公民人数将近1亿，更多 是今天的两倍。随着现代世界的人口统计的持续偏见，理解 在生物医学研究中，减轻衰老过程变得越来越重要。老化 在过去的25年中，研究人员已经发现了许多发现，并证明了衰老的减慢可以 预防或延迟形成许多疾病并改善整体健康状况。其中许多保存 最初使用线虫Caenorhabditis秀丽隐杆线虫发现了“寿命途径” 操纵和简短的寿命使老化的研究受益。 这些备受推崇的出版物中的许多已经确定了多种遗传途径 神经系统对压力的感知具有不同的信号网络和下游效应 尽管这些研究提供了细胞信号传导的大量证据 调节衰老，对于多个寿命途径是常见的，它们缺乏特定的信号，接收器，中性 圆圈和下游效应涉及。其中一些研究报告了重要的 神经递质5-羟色胺是在代谢变化上游的必要信号分子 周围组织，这证实了我将在此提案中提供的初步数据。更具体地说，我们的 数据表明，最研究的寿命干预饮食限制（DR）部分通过细胞起作用 秀丽隐杆线虫中食物的气味抑制的非自治信号通路。我们进一步发现博士 导致诱导肠道基因，含黄素单加氧酶-2（FMO-2），这既是必要的又 足以改善健康范围，抗压力和寿命。我们还观察到FMO-2和 寿命的延伸都取决于血清能信号传导，可以通过血清素概括 拮抗剂药物，misanserin。 该项目将阐明由于缺乏食物而引发的细胞非自治途径的成分 最终导致肠道FMO-2诱导和寿命的延伸。为此，我将确定 启动信号级联的血清素能神经元（AIM 1），并确定哪个神经元接受该神经元 信号（AIM 2）。从这里，我将发现5-羟色胺释放下游发生的信号事件（或 缺席）使用多种筛选方法（AIM 3）。总的来说，这些目标将增强我们的 对修饰老化的高度组成信号通路的理解。我研究的最终目标 是探索这里获得的生物学见解，以发展增加人类健康状况的理论。