Determining the neural mechanisms of mechanosensory food perception in DR-mediated longevity

确定 DR 介导的长寿中机械感觉食物感知的神经机制

• 批准号: 10749150
• 负责人: Elizabeth Sarah Dean
• 金额: $ 4.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749150
• 关键词: Address; Afferent Neurons; Age of Onset; Aging; Animals; Behavior; Biogenic Amines; Biological Assay; Caenorhabditis elegans; Cells; Cellular Structures; Cues; Data; Disease; Dopamine; Eating; Elements; Environmental Risk Factor; FMO2; Fasting; Fertility; Food; Genes; Genetic; Genetic Transcription; Geroscience; Goals; Growth; Health; Human; Intake; Interneurons; Intervention Studies; Intestines; Knock-out; Knowledge; Laboratories; Longevity; Malnutrition; Maps; Mediating; Methods; Nematoda; Nervous System; Neurons; Neuropeptide Receptor; Neuropeptides; Neurotransmitter Receptor; Neurotransmitters; Nutrient; Pathway interactions; Perception; Peripheral; Persons; Pharmacologic Substance; Polystyrenes; Population; Production; Protocols documentation; Proxy; RNA Interference; Regulation; Reporter; Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Smell Perception; Testing; Tissues; Touch sensation; Tyramine; Visualization; Work; age related; dietary requirement; dietary restriction; dopaminergic neuron; experience; food environment; healthspan; improved; insight; knock-down; lifestyle intervention; longevity gene; mimetics; model organism; mutant; neural circuit; neuromechanism; neurotransmission; neurotransmitter release; novel; prevent; receptor; reduced food intake; response; sensory system; time use; transmission process; tyramine receptor

Project Summary: The field of geroscience has identified multiple genetic, pharmaceutical, and lifestyle interventions that promote longevity and delay the onset of age-related disease. One of the most studied of these interventions is Dietary Restriction (DR), or a reduction in nutrient intake that does not cause malnutrition. DR can extend lifespan and healthspan across taxa, and many of the genetic mechanisms of DR were originally discovered in the nematode Caenorhabditis elegans. Unfortunately, dietary restriction is not a realistic solution to prevent age-related disease on a population level because following a DR protocol is very difficult for most people and because the benefits of DR can be blunted by environmental factors. For example, exposing fasted animals to food smells decreases the efficacy of DR in multiple model organisms. In C. elegans, food smells are perceived by sensory neurons that initiate circuits leading to neurotransmitter release from serotonergic and dopaminergic neurons. Signaling from these bioamine neurotransmitters ultimately conveys food availability information to the intestine through cell nonautonomous signaling. In the intestine, this signal suppresses the expression of fmo-2, a gene required for DR-mediated longevity. In the preliminary data collected for this proposal, we found that a second mode of food perception, mechanosensation of food, also suppresses DR-mediated fmo-2 induction and longevity in C. elegans. Much like food smell, mechanosensory suppression of DR requires the production of bioamine neurotransmitters to drive cell nonautonomous regulation of peripheral longevity genes. This project will identify key neurons and signaling components of the cell nonautonomous signaling pathway through which mechanosensory food perception regulates aging. To map this circuit, I will first identify the dopaminergic and tyraminergic neurons activated by mechanosensory food perception and determine whether mechanosensation increases or suppresses release of these neurotransmitters (Aim 1). Next, I will investigate elements of this pathway downstream of bioaminergic neurons by 1) determining the bioamine receptor-expressing interneurons directly downstream of the bioaminergic signal, and 2) identifying neuropeptides and neuropeptide receptors through which information about the food environment is conveyed to the intestine (Aim 2). Together, these aims will enhance our understanding of how different modes of food perception regulate aging through conserved signaling elements. Ultimately, we can use this information to create pharmaceuticals that mimic the benefits of dietary restriction regardless of environmental food cues.

项目摘要： Geroscience领域已经确定了多种遗传，药物和生活方式干预措施 这可以促进寿命并延迟与年龄有关的疾病的发作。其中最受过研究的之一 干预措施是饮食限制（DR），或减少营养摄入量不会导致 营养不良。 DR可以延长寿命和健康范围，跨分类单元以及许多遗传 DR的机制最初是在线虫秀丽隐杆线虫中发现的。 不幸的是，饮食限制并不是预防年龄相关疾病的现实解决方案 人口水平，因为遵循DR协议对大多数人来说非常困难，并且因为 DR的好处可能会被环境因素所削弱。例如，将禁食动物暴露于 食物气味降低了DR在多种模型生物中的功效。在秀丽隐杆线虫中，食物的气味是 感官神经元感知的，启动电路导致神经递质从 血清素能和多巴胺能神经元。这些生物胺神经递质发出的信号最终 通过细胞非自主信号传导将食物的可用性信息传达给肠道。在 肠，该信号抑制了FMO-2的表达，FMO-2是DR介导的寿命所需的基因。 在该提案收集的初步数据中，我们发现第二种食物感知模式， 食物的机械敏化，还抑制了C. 秀丽隐杆线。就像食物的气味一样，机械感觉抑制DR需要生产 生物胺神经递质驱动外周寿命基因的非自主调节。 该项目将识别单元非自主信号的关键神经元和信号成分 机械感觉食品感知调节衰老的途径。要绘制该电路，我将 首先识别由机械感觉食品激活的多巴胺能和酪蛋白能神经元 感知并确定机械密度是否增加或抑制了这些的释放 神经递质（AIM 1）。接下来，我将调查该途径下游的元素 通过1）直接确定表达生物胺受体的中间神经元的生物胺能神经元 生物氨基信号的下游，2）识别神经肽和神经肽受体 通过哪些有关食物环境的信息传达给肠道（AIM 2）。一起， 这些目标将增强我们对不同食物感知方式如何调节衰老的理解 通过保守的信号元素。最终，我们可以使用这些信息来创建 无论环境食品提示如何，都可以模仿饮食限制的药物。