Eating and Sleeping: How neuronal SKN-1/Nrf regulates satiety using the worm C. elegans.

暴饮暴食会导致严重的健康并发症。因此，了解饱腹感的调节(何时停止进食)很重要。这个项目的重点是这些生物决定是如何发挥作用的，以便它们能够被利用来改善人类的健康和健身。有关食物的信息是通过感觉神经系统获得的，并与来自身体的与饥饿或饱腹感有关的内部暗示相结合。这些信号的整合控制了食物的摄入量，维持了体内平衡，预防了疾病。我们在线虫线虫身上研究了这一点，线虫有一个完整的神经系统，并配备了一系列强大的遗传、分子和行为工具。在线虫中，化学感觉神经元感知食物，并通过荷尔蒙将信息传递给动物的其他部位，以控制行为和生理。我们的实验室发现，SKN-1，相当于蠕虫的哺乳动物NRF，在两个ASI神经元中作用，感知食物和控制饱腹感。为了实现这一点，SKN-1整合了胰岛素和转化生长因子-B信号，并促进了能量稳态所需的强大的线粒体网络。Skn-1也是一个典型的长寿基因(Tullet et al，2008)，由于食物摄入量与疾病(如糖尿病、心血管疾病)有很大关系，通过研究Skn-1‘S的神经学角色，我们不仅将确定它在食物相关行为中的作用，还将确定它与食物相关行为、寿命和衰老相关健康之间的重要联系。该项目使用各种技术：遗传学、行为分析、分子生物学和各种显微镜(包括共焦显微镜和透射电子显微镜)来深入研究所涉及的潜在的遗传和生物过程。学生将绘制神经元回路图，识别SKN-1的新的遗传交互作用，并充分探索饱腹感中断的生理效应。由于NRF在哺乳动物大脑中对调节食物相关行为非常重要的区域中表达，该项目将为我们看待NRF功能的方式提供一个阶段性的改变。

Over-eating can lead to serious health complications. So understanding satiety regulation (when to stop eating) is important. This project focuses on how these biological decisions work so that they can be harnessed to improve human health and fitness. Information on food is obtained via the sensory nervous system and integrates with internal cues from the body relating to hunger or satiety. Integration of these signals controls food intake, maintains homeostasis and prevents disease. We study this in the nematode worm C. elegans which have a fully mapped nervous system, and come complete with a selection of strong genetic, molecular and behavioural tools. In C. elegans, chemosensory neurons sense food and relay information to the rest of the animal via hormones to control behaviour and physiology. Our lab has found that SKN-1, the worm equivalent of mammalian Nrf, acts in two ASI neurons to sense food and control satiety. To achieve this SKN-1 integrates insulin and TGF-B signalling and promotes a robust mitochondrial network required for energy homeostasis. SKN-1 is also a well-characterised longevity gene (Tullet et al, 2008), and as food intake has massive implications for disease (e.g. diabetes, cardiovascular disease), via studying SKN-1's neurological role we will not only define its role in food-related behaviour but also important links between food-related behaviour, longevity, and agerelated health. This project uses a variety of techniques: genetics, behavioural assays, molecular biology, and a variety of microscopy (including confocal and TEM) to delve into the underlying genetic and biological processes involved. The student will map the neuronal circuits, identify novel genetic interactors of SKN-1, and fully explore the physiological effects of disrupted satiety. As Nrf is expressed in regions of the mammalian brain important for regulating food-related behaviour, this project will provide a step change in the way we view Nrf function.