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

基本信息

批准号：
9812750
负责人：
Hillary Ann Miller
金额：
$ 3.73万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/9812750
关键词：
Address Adenylate Cyclase Aging 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 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 Process 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 confocal imaging 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

项目摘要

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。预计到2050年，美国65岁以上公民数量将达到近1亿，更多随着现代世界人口结构的不断老龄化，理解力的增长超过了两倍。减轻衰老过程在生物医学研究中变得越来越重要。研究人员在过去 25 年里取得了许多发现，并证明延缓衰老可以预防或延缓许多疾病的形成并改善整体健康状况。 “长寿途径”最初是通过线虫秀丽隐杆线虫发现的，该线虫很容易遗传操纵和短暂的寿命有利于衰老研究。许多这些备受推崇的出版物已经确定了将神经系统对压力的感知具有独特的信号网络和下游效应器虽然这些研究提供了细胞间信号传导的大量证据。调节衰老并且是多种长寿途径所共有的，它们缺乏特定的信号、受体、神经其中一些研究报告了重要的电路和下游效应器。神经递质血清素作为代谢变化上游必需的信号分子外周组织，这证实了我将在本提案中提供的初步数据，更具体地说，是我们的。数据显示，研究最深入的长寿干预措施——饮食限制（DR），部分通过细胞发挥作用我们进一步发现 DR 被线虫中的食物气味抑制。导致肠道基因的诱导，即含有黄素的单加氧酶-2 (fmo-2)，这既是必需的，也是我们还观察到 fmo-2 和的诱导作用足以改善健康寿命、抗压能力和寿命。寿命的延长既依赖于血清素信号传导，又可以通过血清素来概括拮抗药，米安色林。该项目将阐明由食物缺乏引发的细胞非自主途径的组成部分最终导致肠道 fmo-2 诱导并延长寿命。启动信号级联的血清素能神经元（目标 1），并确定哪个神经元接收该信号信号（目标 2）。从这里，我将发现血清素释放（或）下游发生的信号事件。缺席）使用多种筛选方法（目标 3）。对改变衰老的高度保守的信号通路的理解是我研究的最终目标。的目的是利用在这里获得的生物学见解来开发延长人类健康寿命的治疗方法。