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Thyrotrophin signalling at the core of photoperiodic time-measurement

促甲状腺激素信号传导是光周期时间测量的核心

基本信息

批准号：
BB/G004463/1
负责人：
David Hazelrigg
金额：
$ 65.61万
依托单位：
University of Aberdeen
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FG004463%2F1
关键词：
Thyrotrophin signalling core photoperiodic time

项目摘要

Life on Earth has to cope with constantly changing environments. Some of this change is predictable, due to the daily light dark cycle, or to the annual cycle of seasonal change, and animals have evolved biological clocks to optimise their responses to rhythmic environments. These clocks are synchronised primarily through their responses to environmental lighting. In mammals, a key part of the seasonal timing process is the production of a hormone, called melatonin, by the pineal gland. Melatonin is only produced at night, in a temporal pattern that reflects the night-length, and changes in its pattern of production and secretion are known to be a key part of the process whereby animals time seasonal cycles of breeding, moulting and hibernation. Understanding of the genetic mechanisms elements underlying this physiology is of increasing importance since global changes in temperature are predicted to have profound disruptive effects on seasonal timing. This project focusses on the proposal that the mechanisms of melatonin action in mammals, actually depend on melatonin's effects on brain sensitivity to another hormone called thyroid hormone. Thyroid hormone is well known for its effects on animals' 'metabolic rate' - their rate of living, which is essentially the ultimate focus of seasonal changes such as entry into hibernation. So the concept that seasonal changes depend on modulation of the influence of thyroid hormone is intuitively attractive. The effects of melatonin in which we are interested are actually highly localised to the base of the brain, at the interface between the hypothalamus and the pituitary. This region of the brain is specifically concerned with metabolic control, and the timing of breeding. Here, we have identified a link between melatonin-sensitive cells in the pituitary and cells in the adjacent hypothalamus which control thyroid hormone levels in this area. This link is the local production of another hormone called thyroid stimulating hormone (TSH) by melatonin responsive cells, which acts on adjacent hypothalamic brain cells carrying specialised 'receptors' for TSH. The project wishes to explore the importance of this link, in terms of the ways in which melatonin controls TSH production, and the consequences of TSH acting on the adjacent hypothalmus. This project is of considerable interest because the mechanism we are exploring appears to have features in common with that in birds and amphibians, suggesting that it may be an ancient core mechanism. Additionally the novel concept of local actions of TSH by the route we describe has biomedical relevance since several metabolic disorders, including Grave's Disease, stem from abnormal TSH signalling.

地球上的生命必须科普不断变化的环境。有些变化是可以预测的，这是由于每天的光暗周期，或者季节变化的年度周期，动物已经进化出生物钟来优化它们对有节奏环境的反应。这些时钟主要通过它们对环境照明的反应来同步。在哺乳动物中，季节性时间过程的一个关键部分是松果体产生一种称为褪黑激素的激素。褪黑激素仅在夜间产生，其时间模式反映了夜晚的长度，并且已知其产生和分泌模式的变化是动物对繁殖，蜕皮和冬眠的季节性周期进行计时的过程的关键部分。了解这种生理学的遗传机制元素越来越重要，因为全球温度的变化预计会对季节性时间产生深刻的破坏性影响。该项目的重点是建议褪黑激素的作用机制在哺乳动物中，实际上取决于褪黑激素对大脑敏感性的影响，另一种激素称为甲状腺激素。众所周知，甲状腺激素会影响动物的“代谢率”--它们的生存率，这基本上是季节变化（如进入冬眠）的最终焦点。因此，季节变化取决于甲状腺激素影响的调节的概念直观上是有吸引力的。我们感兴趣的褪黑激素的作用实际上高度局限于大脑的底部，在下丘脑和垂体之间的界面。大脑的这个区域特别关注代谢控制和繁殖的时机。在这里，我们已经确定了垂体中的褪黑激素敏感细胞和邻近的下丘脑中控制该区域甲状腺激素水平的细胞之间的联系。这种联系是由褪黑激素反应细胞局部产生的另一种称为促甲状腺激素（TSH）的激素，它作用于邻近的下丘脑脑细胞，这些脑细胞携带专门的TSH“受体”。该项目希望探索这种联系的重要性，在褪黑激素控制TSH产生的方式，以及TSH作用于相邻下丘脑的后果。这个项目非常有趣，因为我们正在探索的机制似乎与鸟类和两栖动物的机制有共同的特征，这表明它可能是一个古老的核心机制。此外，TSH通过我们描述的途径局部作用的新概念具有生物医学相关性，因为包括格雷夫斯病在内的几种代谢紊乱源于异常TSH信号传导。