MICA: Investigating kisspeptin receptor signalling to improve the treatment of reproductive disease

Kisspeptin是下丘脑生殖激素分泌的中枢控制者。我们小组的研究已经确定了一些生殖疾病，将受益于kisspeptin为基础的治疗方法。然而，关于kisspeptin如何与其受体相互作用仍有许多未解之谜。例如，已知给予过多的kisspeptin会降低kisspeptin诱导激素刺激的能力。此外，服用时的雌激素水平会影响对kisspeptin的激素反应。此外，已经产生了许多通过kisspeptin受体起作用的新药。然而，这些基于kisspeptin的新药物的确切方式或雌激素如何与kisspeptin受体相互作用尚未得到充分描述。因此，我们将开展研究以了解天然kisspeptin和新开发的作用于kisspeptin受体的药物如何在细胞内发挥作用，这种作用在过度刺激时如何改变，以及雌激素水平变化对这些过程的影响。在这项提案中，我们已经召集了来自全球各地的专家团队进行尖端实验，以更好地了解kisspeptin受体的信号传导。我们将与一个行业合作伙伴合作，测试一种仍在开发中的基于kisspeptin的口服药物，以及其他最近开发的kisspeptin受体刺激剂。我们将使用下丘脑闭经（月经减少和生育能力低下的最常见原因之一）的动物模型来制定使用kisspeptin为基础的治疗方案，可用于恢复生殖健康。综上所述，有必要更好地了解kisspeptin和基于kisspeptin的药物对kisspeptin受体的作用。这项工作将使我们能够制定使用kisspeptin或kisspeptin类药物的治疗方案，从而改善对患有生殖障碍的患者的护理。

Kisspeptin is the central controller of reproductive hormone secretion from the hypothalamus. Our group's research has identified a number of reproductive disorders that would benefit from treatment using kisspeptin based therapies. However, there remain many unanswered questions as to how kisspeptin interacts with its receptor. For example, it is known that giving too much kisspeptin can reduce the ability of kisspeptin to induce hormonal stimulation. Additionally, levels of oestrogen at the time of administration can affect the hormonal response to kisspeptin. Moreover, a number of new drugs have been generated that act through the kisspeptin receptor. However, the precise way by which these new kisspeptin based drugs or how oestrogen interacts with the kisspeptin receptor has not been fully described.Therefore, we will conduct research to understand how natural kisspeptins and newly developed drugs that act on the kisspeptin receptor exert their effects inside cells, how this is altered in times of excessive stimulation, and the effect of changes in oestrogen levels on these processes. In this proposal, we have assembled a team of experts from across the globe to conduct cutting edge experiments to better understand signalling at the kisspeptin receptor. We will work with an industry partner to test an oral kisspeptin based drug that is still in development, as well as other recently developed kisspeptin receptor stimulators. We will use an animal model of hypothalamic amenorrhoea (one of the commonest causes of loss of periods and subfertility) to develop a protocol using a kisspeptin-based therapy that can be used to restore reproductive health. In summary, it is essential to better understand the action of kisspeptin and kisspeptin-based drugs at the kisspeptin receptor. This work will enable us to develop treatment protocols using kisspeptin or kisspeptin-like drugs that will improve the care of patients suffering from reproductive disorders.