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，饱腹感信号可以防止进食不需要的食物。C.线虫也可能会产生饱腹感：当蠕虫饥饿24小时，然后再进食6小时时，进食动作和探索行为就会减少。本研究的目的是定义C。通过基因筛选识别和表征途径的组成部分来控制食欲。待检验的假设是：（1）蠕虫被诱导消耗过量食物后变得饱食，以及（2）饱食通过特定的一种或多种分子途径影响行为。这些假设将通过3个具体目标进行测试：目标1：描述饱腹感的行为机制。Subaim 1：使用在进食或营养吸收方面有缺陷的不饱突变，我们将确定饥饿/再喂养蠕虫的进食运动和运动活动的减少是否直接反映了它们的饱足状态。Subaim 2：使用不同的低质量和高质量的食物来源，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。目的2：鉴定饱食行为缺陷的突变体。通过对在饥饿/再喂养后与野生型相比具有增加的进食运动和运动活性的突变体进行遗传筛选，将鉴定饱腹感信号传导途径的组分。目标3：测试候选饱腹感信号。当外源性给予小鼠时，胆囊收缩素和肽YY减少膳食量。我们将通过反向遗传学方法，如RNA干扰，靶向这些神经肽受体的同源物。我们将研究候选受体的敲除或过表达是否会增加或减少膳食量

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