The chronobiology of somatosensation

我们的研究小组研究了调节感觉神经元形态(即对机械、温度和伤害性刺激的反应)的神经免疫相互作用。这些神经元的不同亚群表达的离子通道介导了许多这些效应，最近发现，免疫因素的存在直接或间接地改变了这些效应，包括细胞因子/趋化因子、金属蛋白酶和生长因子。在这份新的发现拨款申请中，我们将以我实验室的最新发现为基础，研究时间生物节律如何调节神经免疫通讯，并改变体内的躯体感觉行为和体外感觉神经元的活动。*我们研究计划的总体目标是确定调节神经元激活/敏化的新机制和细胞内信号通路。虽然我们通常使用损伤模型来探索这些相互作用，但越来越明显的是，由于确定了大量的候选对象，很难精确定位感兴趣的特定目标。我的实验室最近的一项发现表明，在小鼠的黑暗阶段，对辐射热刺激的热敏感性是不存在的。这一新的和令人兴奋的发现表明，时间生物学节律可以用于健康、未受伤的动物，以确定可能调节这些行为影响的配体-受体相互作用，而不必依赖于损伤/疾病模型。其他研究小组已经证明，离子通道/受体和免疫介体在幼稚状态下受到昼夜节律的调节。因此，我们假设特定的神经免疫细胞内信息传递途径和受体-配体对受到时间生物节律的调节，以改变离子通道活性和躯体感觉功能。这项建议的具体目的是：*1.通过关注外部(光)和内部(分子时钟)线索来表征体感的昼夜节律控制[Phd1，Msc1，Bsc1，2]；*2.确定对躯体感觉的时间生物学控制有贡献的细胞类型(S)[Phd1，Msc2，Bsc3]；以及*3.识别由时间生物节律改变的改变离子通道活动/功能的分子线索[Phd1，Msc3，Bsc4，5]。*生物节律控制几乎所有动物的各种生理过程；感觉神经元表达的离子通道/受体与分泌的免疫介体之间的相互作用改变了物种间的行为活动。因此，这项研究可以通过促进我们对三个看似不同的系统之间发生的相互作用的理解，来影响神经科学、免疫学和时间生物学领域。这里概述的研究计划还将通过培训研究生和本科生HQP收集、分析和传播使用各种现代生物和生化技术收集的数据，从而使加拿大和加拿大人受益。

Our research group investigates neuro-immune interactions that modulate sensory neuron modalities (i.e. responses to mechanical, thermal and nociceptive stimuli). Ion channels expressed by distinct subsets of these neurons mediate many of these effects, and have recently been found to be directly and indirectly altered by the presence of immune factors including cytokines/chemokines, metalloproteases, and growth factors. In this new Discovery Grant submission, we will build on recent discoveries in my laboratory to investigate how chronobiological rhythms can regulate neuro-immune communication and alter somatosensory behaviour in vivo and sensory neuron activity in vitro. ******The over-arching goal of our research program is to identify novel mechanisms and intracellular signalling pathways that regulate neuronal activation/sensitization. While we commonly used injury models to explore these interactions, it has become increasingly clear that it is difficult to pinpoint specific targets of interest, due to the large number of candidates identified. A recent finding in my laboratory shows that thermal sensitivity to a radiant heat stimulus is absent during the dark phase in mice. This novel and exciting finding suggests that chronobiological rhythms can be used in healthy, uninjured animals to identify ligand-receptor interactions that may modulate these behavioural effects instead of having to rely injury/disease models. Other groups have shown that ion channels/receptors and immune mediators are modulated by circadian rhythms in the naïve state. Therefore, we hypothesize that specific neuro-immune intracellular messaging pathways and receptor-ligand pairs are regulated by chronobiological rhythms to alter ion channel activity and somatosensory function. The specific Aims of this proposal are to:***1. Characterize the circadian control of somatosensation, by focusing on external (light) and internal (molecular clock) cues [PhD1, MSc1, BSc1,2];***2. Determine the cell type(s) contributing to chronobiological control of somatosensation [PhD1, Msc2, BSc3]; and***3. Identifying the molecular cues altered by chronobiological rhythms to alter ion channel activity/function [PhD1, MSc3, Bsc4,5].******Biological rhythms control various physiological processes in almost all animals; interactions between ion channels/receptors expressed by sensory neurons and secreted immune mediators alter behavioural activity across species. Thus, this study can impact the fields of neuroscience, immunology, and chronobiology by advancing our understanding of the interactions that occur between the three seemingly disparate systems. The research plan outlined here will also benefit Canada and Canadians by training graduate and undergraduate HQP in the collection, analysis and dissemination of data gathered using a diverse set of modern biological and biochemical techniques.