Satiety signaling in Caenorhabditis elegans

描述(由申请人提供)： 在人类中，不受控制的食欲和随后的暴饮暴食会导致肥胖和肥胖相关疾病。食欲在一定程度上是由饱腹感信号控制的，这些信号防止了不需要的食物的消费。线虫也可能会饱食：当蠕虫饥饿24小时，然后重新喂养6小时时，摄食动作和探索行为会减少。这项研究的目的是通过基因筛选识别和表征该途径的组成部分，以确定控制食欲的线虫饱腹感信号。要测试的假设是(1)被诱导摄入过量食物的蠕虫变得饱足，(2)饱腹感通过一个或多个特定的分子途径影响行为。这些假说将通过3个具体目标进行检验：目标1：描述饱腹感的行为机制。Subaim 1：使用在摄食或营养吸收方面有缺陷的永无止境的突变，我们将确定饥饿/再灌食蠕虫的摄食运动和运动活动的减少是否直接反映了它们的饱腹感状况。Subaim 2：使用不同的低质量和高质量食物来源，我们将操纵饱腹感的条件，并检查进食动作和运动活动是否取决于食物质量。目标2：确定在饱腹感行为上有缺陷的突变体。通过对饥饿/再摄食后与野生型相比具有更多摄食运动和运动活性的突变体的遗传筛选，将识别饱腹感信号通路的组成部分。目标3：测试候选人的饱腹感信号。外源性给药时，缩胆囊素和YY肽可减少小鼠的进食量。我们将通过反向遗传方法，如RNA干扰，来靶向这些神经肽的受体同源物。我们将研究候选受体的敲除或过度表达是否会增加或减少膳食

DESCRIPTION (provided by applicant): In humans, uncontrolled appetite and subsequent overeating cause obesity and obesity-associated diseases. Appetite is controlled in part by satiety signals that prevent the consumption of unneeded food. C. elegans may also be subject to satiety: feeding motions and exploratory behavior are reduced when worms are starved for 24 hours, then refed for 6 hours. This study aims to define C. elegans satiety signals that control appetite by identifying and characterizing the components of the pathway via a genetic screen. The hypotheses to be tested are (1) that worms induced to consume excess food become satiated, and (2) that satiety influences behavior via a specific molecular pathway or pathways. These hypotheses will be tested through 3 specific aims; Aim 1: Characterize the behavioral mechanisms of satiety. Subaim 1: Using insatiable mutations which are defective in feeding or nutrient absorption, we will determine whether reduction of feeding motions and locomotive activity in starved/refed worms are direct reflections of their satiety status. Subaim 2: Using different low and high-quality food sources, we will manipulate the conditions of satiety and examine whether feeding motions and.locomotive activity depend on food quality. Aim 2: Identify mutants that are defective in satiety behavior. Through genetic screening for mutants that have increased feeding motions and locomotive activity compared to wild type after starvation/refeeding, components of the satiety signaling pathway will be identified. Aim 3: Test candidate satiety signals. Cholecystokinin and peptide YY decrease meal size when exogenously administered to mice. We will target homologs of receptors for these neuropeptides by reverse genetic methods such as RNA interference. We will examine whether the knockout or overexpression of candidate receptors increases or decreases meal size