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: 9979341
• 负责人: Tadahiro Goda
• 金额: $ 23.73万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979341
• 关键词: Behavior; Behavioral; Bioinformatics; Biological Assay; Biological Models; Body Temperature; Body Temperature Changes; Calcitonin Receptor; Calcium Oscillations; Candidate Disease Gene; Cells; Circadian Rhythms; Clock protein; Data; Disease; Dorsal; Drosophila garnet protein; Drosophila genus; Exhibits; Foundations; Funding Opportunities; G-Protein-Coupled Receptors; Gene Expression Profile; Genes; Goals; Grant; Health; Homeostasis; Homologous Gene; Hour; Human body; Jet Lag Syndrome; Luciferases; Mammals; Mediating; Mediator of activation protein; Metabolism; Molecular; Morphology; Motor Activity; Mus; Neurons; Outcome; Outcome Study; Output; Pathway interactions; Periodicity; Peripheral; Play; RNA Interference; Regulation; Resolution; Role; Services; Sleep; Sleep Disorders; Sleep disturbances; Solid; Temperature; Wakefulness; Work; circadian pacemaker; comparative; expectation; fly; high throughput screening; in vivo; innovation; insight; knock-down; neural circuit; neuromechanism; novel; preference; relating to nervous system; selective expression; shift work; suprachiasmatic nucleus; transcriptome; transcriptome sequencing; transcriptomics

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.

项目摘要：该项目的具体目标是确定新的分子和神经机制。 昼夜节律，重点是体温节律(BTR)背后的调节机制。在……里面 在人类中，BTR的典型特征是清醒时体温上升，睡眠时体温下降，是一种 生物钟的强劲输出。此外，Btr还维持内稳态，包括 哺乳动物的新陈代谢和睡眠，并携带外周生物钟。重要的是，BTR是以一种方式进行监管的 有别于运动活动节律；因此，BTR的神经机制和回路与 运动活动节律的那些。 在这项R21探索性拨款中，我们将重点放在BTR特定的神经机制和电路上；为此，我们 将利用果蝇的温度偏好行为作为一种创新和稳健的实验输出形式。 我们以前证明了果蝇表现出温度偏好节律(TPR)，在TPR中， 首选温度在白天升高，在从白天到夜间的过渡中降低。不像 哺乳动物产生内热来调节BTR，果蝇依靠行为策略来调节 他们每天的体温都在变化。因此，果蝇TPR通过物理性选择产生BTR 较佳的环境温度。 通过对果蝇TPR行为的研究，我们最近发现DH31R是一种果蝇G蛋白-DH31R。 时钟神经元上的偶联受体，介导TPR。此外，我们确定最接近的同源基因 在小鼠的DH31R中，降钙素受体(CALCR)在视交叉上核(SCN)中表达 调解BTR。重要的是，果蝇的DH31R和小鼠的CALCR都不参与运动活动的节律性。 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，还受到调控。 我们的数据表明，Fly TPR的调控机制可能与哺乳动物的BTR和副产物类似 反之亦然；因此，我们预计控制果蝇TPR的特定神经和分子机制是保守的。 在哺乳动物身上。提出了两个具体的目标：在目标1中，我们将识别选择性和 在DN2s中高表达。在目标2中，我们将确定在TPR中起重要作用的候选基因。 在完成拟议的工作后，我们的期望是识别出对 调节TPR，包括TPR神经回路的动态变化。此外，我们对果蝇的检查 TPR行为将包括一种创新的、健壮的和复杂的方法来阐明神经 调节BTR的机制。预计这项研究的结果将为 了解哺乳动物BTR的机制，为治疗BTR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。