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Thermal sensory mechanisms involved in body temperature regulation

参与体温调节的热感觉机制

基本信息

批准号：
BB/L002787/1
负责人：
Peter Anthony McNaughton
金额：
$ 51.2万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL002787%2F1
关键词：
Thermal sensory mechanisms involved body

项目摘要

In a cold environment mammals reduce blood flow to the skin in order to conserve heat, while in a hot environment sweating reduces body temperature. It is well established that the reduction in skin blood flow in a cold environment is mediated by noradrenergic sympathetic nerves, which innervate blood vessels and release noradrenaline in order to cause vasoconstriction in response to cold. Conversely, cholinergic sympathetic nerves innervate sweat glands to produce cooling in a hot environment. The heat and cold-sensitive mechanisms - the "thermostats" - which drive activity in these two divisions of the sympathetic nervous system are, however, unknown. In preliminary experiments we have found an ion channel in sympathetic neurons which is directly activated by cold, while a different ion channel expressed in parasympathetic neurons, which are cholinergic, is directly activated by warmth. The heat and cold-sensitive ion channels underlying these responses are novel thermosensory mechanisms, as they are not activated by any of the agonists for known thermally sensitive ion channels. The discovery of these novel thermally sensitive mechanisms will now allow us to characterize their electrical properties. We will then proceed to determine their molecular basis using RNA sequencing, in which we will compare the mRNA expressed in specific cold-sensitive and warm-sensitive neuronal populations with similar populations which are not thermally sensitive, and so will determine which ion channel mRNAs are differentially expressed. Finally, we will clone and express the ion channels that we have identified in order to check that the properties of the cloned gene are the same as those expressed in thermally-sensitive neurons.In parallel we will investigate the thermally sensitive mechanism which determines the mammalian core body temperature. Warmth-activated neurons are known to be present in the pre-optic nucleus of the anterior hypothalamus and to be important in regulating body temperature. We will isolate neurons from this region and will study their activation by thermal stimuli. Is the mechanism the same as the warmth-activated mechanism that we have discovered in cholinergic neurons? We will examine the mRNA expressed in these neurons using in situ hybridization, and if the same channels are expressed then we will have an answer to an important problem in biology, namely how mammals sense their core temperature. If the mechanism is not the same then we will isolate mRNA from populations of thermally sensitive neurons and will compare the mRNA abundance with that in adjacent non-thermally sensitive to clone the thermoregulatory gene in a similar approach to that outlined above.

在寒冷的环境中，哺乳动物减少皮肤的血流量以保存热量，而在炎热的环境中，出汗会降低体温。在寒冷的环境中，皮肤血流量的减少是由去甲肾上腺素能交感神经介导的，它支配血管并释放去甲肾上腺素，以引起血管收缩以应对寒冷。相反，胆碱能交感神经支配汗腺在炎热的环境中产生降温作用。然而，驱动交感神经系统这两部分活动的热和冷敏感机制——“恒温器”——尚不清楚。在初步实验中，我们发现在交感神经细胞中有一个离子通道直接被寒冷激活，而在副交感神经细胞中表达的另一个离子通道是胆碱能的，被温暖直接激活。这些反应背后的热敏和冷敏离子通道是一种新的热感机制，因为它们不被任何已知热敏离子通道的激动剂激活。这些新型热敏机制的发现现在将使我们能够表征它们的电学性质。然后，我们将继续使用RNA测序来确定它们的分子基础，其中我们将比较特定冷敏感和热敏感神经元群体中表达的mRNA与不热敏的相似群体，从而确定哪些离子通道mRNA差异表达。最后，我们将克隆并表达我们已经确定的离子通道，以检查克隆基因的特性是否与热敏神经元中表达的相同。同时，我们将研究决定哺乳动物核心体温的热敏机制。已知温暖激活的神经元存在于下丘脑前部的视前核中，在调节体温中起重要作用。我们将从这个区域分离神经元，并研究它们在热刺激下的激活。这种机制和我们在胆碱能神经元中发现的温暖激活机制是一样的吗？我们将使用原位杂交检查这些神经元中表达的mRNA，如果表达相同的通道，那么我们将回答生物学中的一个重要问题，即哺乳动物如何感知其核心温度。如果机制不相同，那么我们将从热敏神经元群体中分离mRNA，并将mRNA丰度与相邻非热敏神经元的mRNA丰度进行比较，以类似的方法克隆温度调节基因。