Exploring the molecular mechanisms of body temperature rhythms through a Drosophila model system

通过果蝇模型系统探索体温节律的分子机制

• 批准号: 10440755
• 负责人: Fumika Hamada
• 金额: $ 20万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440755
• 关键词: Exploring; molecular; mechanisms; body; temperature

PROJECT SUMMARY: The specific goal of this project is to identify novel molecular and neural mechanisms of circadian rhythm, focusing on the regulatory mechanisms that underlie body temperature rhythm (BTR). In humans, BTR is typified by temperature increases during wakefulness and decreases during sleep, and is a robust output of the circadian clock. Furthermore, BTR maintains homeostasis, including the homeostasis of metabolism and sleep, and entrains peripheral clocks in mammals. Importantly, BTR is regulated in a manner distinct from locomotor activity rhythms; therefore, the neural mechanisms and circuits of BTR are separate from those of locomotor activity rhythms. In this R21 exploratory grant, we will focus on BTR-specific neural mechanisms and circuits; to do so, we will use Drosophila temperature preference behavior as an innovative and robust form of experimental output. We previously demonstrated that Drosophila exhibit a temperature preference rhythm (TPR), in which the preferred temperature increases during the day and decreases at the transition from day to night. Unlike mammals, which generate internal heat to regulate BTR, Drosophila rely on behavioral strategies to regulate their daily body temperature changes. Therefore, Drosophila TPR produces BTR through the physical selection of a preferred environmental temperature. Through studies of Drosophila TPR behavior, we recently identified that DH31R, a Drosophila G-protein- coupled receptor in clock neurons, mediates TPR. Furthermore, we determined that the closest homolog of DH31R in mice, calcitonin receptor (CALCR), is expressed in the shell suprachiasmatic nucleus (SCN) to mediate BTR. Importantly, neither DH31R in flies nor CALCR in mice is involved in locomotor activity rhythmicity. These findings provided the first molecular evidence that BTR is regulated apart from locomotor activity rhythms. Our data suggest that fly TPR is likely regulated by mechanisms similar to that of mammalian BTR and vice versa; therefore, we expect that specific neural and molecular mechanisms in control of fly TPR are conserved in mammals. Two specific aims are proposed: In Aim 1, we will Identify gene profiles that are selectively and highly expressed in DN2s. In Aim 2, we will determine candidate genes which play important role in TPR. Upon completion of the proposed work, our expectation is to have identified genes that are important to regulate TPR, including dynamic changes to the TPR neural circuitry. Further, our examination of Drosophila TPR behavior will comprise an innovative, robust, and sophisticated approach to elucidate the neural mechanisms that regulate BTR. The outcome of this study is expected to establish a solid foundation to understand the mechanisms of BTR in mammals, lending important and actionable insights into the treatment of circadian clock diseases, sleep problems, and the health of night-shift workers.

项目概述：本项目的具体目标是确定新的分子和神经机制， 昼夜节律，侧重于体温节律（BTR）的调节机制。在 对于人类来说，BTR的典型特征是在清醒期间温度升高，在睡眠期间温度降低，并且是一种 生物钟的强大输出。此外，BTR维持体内平衡，包括 代谢和睡眠，并在哺乳动物中携带外周时钟。重要的是，BTR是以一种 与运动活动节律不同;因此，BTR的神经机制和回路与 运动活动的节律。 在R21探索性资助中，我们将专注于BTR特定的神经机制和回路;为此，我们 将使用果蝇的温度偏好行为作为一种创新和强大的实验输出形式。 我们以前证明果蝇表现出温度偏好节律（TPR），其中 优选的温度在白天升高，在从白天到夜晚的过渡时降低。不像 哺乳动物产生内部热量来调节BTR，果蝇依靠行为策略来调节 它们每天的体温都在变化因此，果蝇TPR通过物理选择产生BTR 最佳环境温度。 通过对果蝇TPR行为的研究，我们最近发现果蝇G蛋白DH 31 R- 偶联受体在时钟神经元，介导TPR。此外，我们确定， DH 31 R在小鼠中，降钙素受体（CALCR），在壳视交叉上核（SCN）中表达， 介导BTR。重要的是，果蝇中的DH 31 R和小鼠中的CALCR都不参与自发活动节律性。 这些发现提供了第一个分子证据，证明BTR除了运动活动节律外还受到调节。 我们的数据表明，苍蝇TPR可能受到类似于哺乳动物BTR的机制的调节， 反之亦然;因此，我们预期控制果蝇TPR的特定神经和分子机制是保守的 在哺乳动物中。提出了两个具体目标：在目标1中，我们将确定选择性和 在DN 2中高度表达。目的二是确定在TPR中起重要作用的候选基因。 在完成这项工作后，我们的期望是确定对以下方面重要的基因： 调节TPR，包括TPR神经回路的动态变化。此外，我们对果蝇的研究 TPR行为将包括一个创新的，强大的，复杂的方法来阐明神经 调节BTR的机制。这项研究的结果预计将奠定坚实的基础， 了解BTR在哺乳动物中的机制，为BTR的治疗提供重要和可操作的见解。 生物钟疾病、睡眠问题和夜班工人的健康。