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Neonatal programming of pubertal delay: a novel neural interaction between corticotrophin-releasing hormone and kisspeptin

青春期延迟的新生儿编程：促肾上腺皮质激素释放激素和 Kisspeptin 之间的新型神经相互作用

基本信息

批准号：
BB/F007396/1
负责人：
Kevin O'Byrne
金额：
$ 58.05万
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：
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%2FF007396%2F1
关键词：
Neonatal programming pubertal delay novel

项目摘要

Puberty remains one of the biggest mysteries in biology with precious little known about what triggers it. The normal age of puberty is about 10.5 years in girls and 11.5 years in boys, but it is very variable. There is considerable public and medical interest in the causes of very early puberty because of the consequences of a mismatch between the psychological and body changes caused by the early rise in 'the hormones' and the actual level of maturity of the individual. Indeed, recent brain imaging studies have shown that brain maturation extends into the early twenties. Improved diet is thought to underlie the gradual fall in age of puberty onset, but the ever increasing incidence of childhood obesity is accelerating this trend. On the other hand, a delay in puberty can be caused by many factors, including malnutrition, emotional and social deprivation and in particular stress. Early or late onset of puberty can have serious health effects and often raises a great deal of anxiety in the individual or family concerned. Understanding the processes that control the timing of puberty will help in the management and treatment of children affected. Normal puberty starts with activation of a small area in the brain called the hypothalamus that begins to secrete a hormone called gonadotrophin-releasing hormone (GnRH), which sets in motion a cascade of hormonal signals that lead to stimulation of both the ovaries and the testes. The hormones from the developing ovaries or testes drive sexual maturation and the many other physical and emotional changes associated with adolescence. What triggers the activation of the GnRH system in the brain remained a mystery until very recently when it was discovered that a genetic mutation of a particular chemical receptor in the brain of humans stopped them from going into puberty. Similar mutations in animal models caused identical problems. These receptors are activated by a brain chemical named 'kisspeptin'. The scientists who discovered this chemical were working at the Pennsylvania State Medical Centre in Hershey USA and they gave it this name because; Hershey is the location of America's famous chocolate factory and the scientists named it after the chocolate company's signature miniature treat chocolate 'kisses'. Although, kisspeptin is undoubtedly the single most important activator of the GnRH system it now remains to be discovered what triggers the kisspeptin system at puberty. There is growing awareness that adverse early life environments can have major detrimental effects on health and disease later in life. For example, in humans and animals the immediate period after birth is especially dangerous for bacterial infection because the body's immune system is not yet fully developed. Indeed, more than 40% of all human newborn deaths (~1.7 million per year globally) are due to neonatal bacterial infection. Animals that have been exposed to bacterial substances (endotoxins) during the first week of life are more sensitive to stress when they reach adulthood. Additionally these animals display altered immune, metabolic, anxiety, memory and cognition function as adults, which show that early life exposure to bacteria can exert long-term 'programming' effects on a number of body functions. These and other observations have led to the idea of 'developmental origins of health and disease'. In pilot studies using the animal model of early life infection stress we have shown a delay in the onset of puberty. We have also shown a permanent decrease in brain levels of kisspeptin and an increase in brain levels of corticotrophin-releasing hormone (CRH) receptor, the major stress hormone receptor. This provides a unique opportunity not only to discover key interaction between the stress hormone system (CRH) and the trigger system (kisspeptin) that controls the timing of puberty, but may help future developments of more effective treatments for stress-related disorders of puberty.

青春期仍然是生物学上最大的谜团之一，人们对它的触发因素知之甚少。青春期的正常年龄女孩约为10.5岁，男孩约为11.5岁，但差异很大。公众和医学界对青春期过早的原因有相当大的兴趣，因为这是由于“荷尔蒙”的早期升高和个体的实际成熟水平导致的心理和身体变化之间的不匹配造成的后果。事实上，最近的脑成像研究表明，大脑的成熟持续到20岁出头。饮食的改善被认为是青春期开始年龄逐渐下降的基础，但儿童肥胖率的不断上升正在加速这一趋势。另一方面，青春期延迟可能由许多因素造成，包括营养不良、情感和社会剥夺，特别是压力。青春期的提前或延迟可能会对健康产生严重的影响，并往往会在有关个人或家庭中引发极大的焦虑。了解控制青春期时间的过程将有助于对受影响儿童的管理和治疗。正常的青春期始于大脑中名为下丘脑的一小块区域的激活，该区域开始分泌一种名为促性腺激素释放激素(GnRH)的激素，它启动一系列激素信号，导致卵巢和睾丸受到刺激。来自发育中的卵巢或睾丸的荷尔蒙驱动性成熟，以及与青春期相关的许多其他生理和情感变化。直到最近，人们发现人类大脑中一种特定化学受体的基因突变阻止了他们进入青春期，是什么触发了大脑中GnRH系统的激活仍然是一个谜。动物模型中类似的突变导致了相同的问题。这些感受器是由大脑中一种名为“Kispeptin”的化学物质激活的。发现这种化学物质的科学家是在美国好时的宾夕法尼亚州立医疗中心工作的，他们之所以给它取这个名字，是因为好时是美国著名巧克力工厂的所在地，科学家们以巧克力公司标志性的迷你甜点巧克力‘亲吻’来命名它。尽管，kisspeptin无疑是促性腺激素释放激素系统最重要的单一激活剂，但目前还没有发现是什么在青春期触发了kisspeptin系统。人们越来越意识到，不利的早期生活环境可能会对晚年的健康和疾病产生重大有害影响。例如，在人类和动物中，出生后的紧要期对细菌感染特别危险，因为人体的免疫系统还没有完全发育。事实上，超过40%的人类新生儿死亡(全球每年约170万)是由新生儿细菌感染引起的。在生命的第一周暴露在细菌物质(内毒素)中的动物在成年后对压力更敏感。此外，这些动物成年后表现出免疫、新陈代谢、焦虑、记忆和认知功能的改变，这表明早期接触细菌可以对身体的一些功能产生长期的“编程”影响。这些和其他的观察结果导致了“健康和疾病的发育起源”的观点。在使用早期感染应激的动物模型进行的初步研究中，我们发现青春期的开始有延迟。我们还发现大脑中Kispeptin的水平持续下降，而主要应激激素受体--促肾上腺皮质激素释放激素(CRH)受体的水平上升。这不仅提供了一个独特的机会，不仅可以发现应激激素系统(CRH)和控制青春期时机的触发系统(Kispeptin)之间的关键相互作用，而且可能有助于未来开发更有效的青春期应激相关疾病治疗方法。