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

项目摘要： 老年科学领域已经确定了多种遗传、药物和生活方式干预措施 促进长寿和延缓与年龄有关的疾病的发生。其中研究最多的 干预措施是饮食限制（DR），或减少营养摄入量， 营养不良DR可以延长整个分类群的寿命和健康寿命，许多遗传因素 DR的机制最初是在线虫秀丽隐杆线虫中发现的。 不幸的是，饮食限制并不是一个现实的解决方案，以防止与年龄有关的疾病， 因为对于大多数人来说，遵循DR协议非常困难， 环境因素可能会削弱DR的益处。例如，将禁食的动物暴露于 食物气味降低了DR在多种模式生物中的功效。In C.食物的气味 由感觉神经元感知，启动导致神经递质释放的回路， 血清素能和多巴胺能神经元。这些生物胺神经递质的信号最终 通过细胞非自主信号传导将食物可用性信息传递给肠道。在 在肠道中，该信号抑制fmo-2的表达，fmo-2是DR介导的长寿所需的基因。 在为这项提议收集的初步数据中，我们发现食物感知的第二种模式， 食物的机械感觉，也抑制DR介导的fmo-2诱导和C. 优雅就像食物气味一样，DR的机械感觉抑制需要产生 生物胺神经递质驱动外周长寿基因的细胞非自主调节。 这个项目将确定关键的神经元和信号组件的细胞非自主信号 机械感觉食物感知调节衰老的途径。为了绘制这个电路，我将 第一次确定由机械感觉食物激活的多巴胺能和酪胺能神经元 感知，并确定机械感觉是否增加或抑制这些释放 神经递质（Aim 1）。接下来，我将研究这条通路下游的元件， 生物胺能神经元通过1）直接测定生物胺受体表达的中间神经元 生物胺能信号的下游，和2）鉴定神经肽和神经肽受体 食物环境的信息通过它传递到肠道（目标2）。在一起， 这些目标将增强我们对不同食物感知模式如何调节衰老的理解 通过保守的信号元件。最终，我们可以用这些信息来创造 这些药物模仿了饮食限制的好处，而不管环境食物的线索。

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.