Regulation and Function of Melatonin Receptors

褪黑激素受体的调节和功能

• 批准号: RGPIN-2016-05697
• 负责人: Niles, Lennard
• 金额: $ 2.26万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=660974
• 关键词: Regulation; Function; Melatonin; Receptors

***The pineal gland in mammals including humans, produces a chemical messenger or hormone called melatonin, which exhibits very low daytime levels, with peak levels present in the circulation at night. This hormone plays an important role in the regulation of circadian rhythms by interacting with the biological clock in the brain. It is involved in modulating numerous other physiological activities including neuroendocrine function, immune responses and reproduction. Moreover, melatonin is a cytoprotective hormone that protects cells against the injurious effects of free radicals and environmental neurotoxins. In order to produce its diverse effects, melatonin travels in the bloodstream to reach the brain or other organs, where it binds to specific sites or receptors, which are located on its target cells. Melatonin binding conveys a signal which results in a cascade of cellular responses, with consequent changes in the function of its target cells and organs. Importantly, older individuals exhibit a significant decrease in their blood levels of this protective hormone, which is thought to be related to the progressive age-related onset of physiological dysfunction.****Our NSERC-funded studies have shown that certain drugs, which alter gene activity by an epigenetic mechanism, cause a significant upregulation or increase in the number of melatonin receptors in the brain and in cultured cells. Epigenetics involves the regulation of gene expression, without changes to the underlying DNA sequence. This research program is aimed at determining how the above mentioned drug-induced increases in melatonin receptors influences the signaling and function of melatonin in the young or aging brain. Melatonin has been shown to increase the formation of new cells in an area of the brain which is essential for cognitive function such as memory and learning. However, the progressive loss of both melatonin and its receptors results in a decrease in activity of the melatonergic system in aging mammals. Given the decline in both cognition and melatonergic activity with aging, it is anticipated that our novel strategy for increasing the number of melatonin receptors coupled with administration of this hormone, will maintain or restore cognition and other essential functions in the aging brain. In addition, this proposal is aimed at clarifying the mechanisms involved in this novel and original strategy for upregulating melatonin receptors in the brain and other target tissues. Clarification of these mechanisms and the functional correlates of melatonin receptor upregulation will be a significant advance in melatonin physiology and provide a base for understanding its diverse roles in mammalian biology. Ultimately, it should be possible to utilize this knowledge in order to preserve melatonin receptor expression and function, thus maintaining the homeostatic benefits of this hormone.******

* 包括人类在内的哺乳动物的松果体产生一种称为褪黑激素的化学信使或激素，其白天水平非常低，夜间循环中存在峰值水平。这种激素通过与大脑中的生物钟相互作用，在昼夜节律的调节中起着重要作用。它参与调节许多其他生理活动，包括神经内分泌功能，免疫反应和生殖。此外，褪黑激素是一种细胞保护激素，保护细胞免受自由基和环境神经毒素的伤害。为了产生其不同的效果，褪黑激素在血液中行进到达大脑或其他器官，在那里它结合到位于其靶细胞上的特定位点或受体。褪黑激素结合传递导致级联细胞反应的信号，从而改变其靶细胞和器官的功能。重要的是，老年人的这种保护性激素的血液水平显着下降，这被认为与生理功能障碍的渐进性年龄相关发作有关。我们NSERC资助的研究表明，某些药物通过表观遗传机制改变基因活性，导致大脑和培养细胞中褪黑激素受体数量显著上调或增加。表观遗传学涉及基因表达的调节，而不改变潜在的DNA序列。该研究计划旨在确定上述药物诱导的褪黑激素受体增加如何影响褪黑激素在年轻或衰老大脑中的信号传导和功能。褪黑激素已被证明可以增加大脑某个区域新细胞的形成，这对记忆和学习等认知功能至关重要。然而，褪黑激素及其受体的逐渐丧失会导致衰老哺乳动物褪黑激素能系统的活性下降。考虑到认知和褪黑激素能活性随年龄增长而下降，预计我们增加褪黑激素受体数量的新策略与该激素的施用相结合，将维持或恢复衰老大脑中的认知和其他基本功能。此外，该提案旨在阐明这种上调大脑和其他靶组织中褪黑激素受体的新颖和原始策略所涉及的机制。 澄清这些机制和功能相关的褪黑激素受体上调将是一个显着的进步褪黑激素生理学，并提供了一个基础，了解其在哺乳动物生物学中的不同作用。最终，应该可以利用这些知识来保护褪黑激素受体的表达和功能，从而保持这种激素的稳态益处。