Regulation of somatotroph development & function by C-type natriuretic peptide (CNP) in humans, cats, mice and zebrafish

生物体的生长是动态平衡的主要组成部分之一。因此，适当地控制生长对所有动物的健康至关重要。内分泌系统通过各种激素，在调节生物体何时需要生长和发育方面发挥着关键作用。调节生长的主要内分泌控制中心是脑下垂体，它是一个豌豆大小的器官，位于大脑的底部。许多已知在脑下垂体发育中起重要作用的基因已经被发现，其中有几个基因是分泌生长激素(GH)的细胞所特有的。脑下垂体肿瘤是人类最常见的颅内肿瘤，每6人中就有1人在死亡时表现出这些生长的证据。垂体瘤和其他垂体瘤一样，会导致许多荷尔蒙分泌受阻，从而影响这些患者的生活质量。我们最近发现，狗和猫等同伴动物都很容易患上这些脑下垂体肿瘤。生长激素是一种主要的脑下垂体激素，对个体的发育和成长极其重要，生长激素的释放通常受到下丘脑(大脑的一部分)以及肝脏等组织释放的其他激素的严格控制。不适当的生长激素释放过高或过低会导致一系列疾病，从婴儿的发育异常到成年人的侏儒症或代谢并发症，甚至增加患某些类型结肠癌的风险。我们最近发现，在脑下垂体中发现的另一种激素，C型利钠肽(CNP)，在人、小鼠和鱼的脑下垂体发育非常早的时候就会产生。我们最近对30个人类垂体腺瘤的研究发现，每个肿瘤都表达CNP和控制其作用的受体，称为GC-B。此外，我们的初步研究表明，用CNP处理垂体细胞可以导致GH生成量的显著增加。我们计划进行的工作，在本申请中详述，将扩大我们对CNP如何影响脑下垂体正常发育和功能的理解。我们将使用五种不同的模型来研究CNP的影响：培养的垂体细胞，在其脑垂体中特别缺乏CNP的小鼠，人类和猫的垂体肿瘤，以及高度多功能的斑马鱼，在这些模型中，我们将沉默编码CNP的基因，并确定其对正常生长的影响。此外，我们的实验室配备了极其高效的基因分析仪，使我们能够在单个样本中测量多达15个不同基因的数量，从而极大地提高了我们从这些非常少量的组织中获得的生产力。这些研究可能揭示CNP在治疗生长障碍方面的作用，既可以作为增加生长受损个体GH释放的一种方式，也可以通过开发药物来阻断CNP的影响，从而减少GH释放。这些发现可能导致生活质量的提高，并降低对后续内分泌疾病的易感性。

The growth of an organism is one of the major components of homeostasis. As such, controlling growth appropriately is vital for the health of all animals. The endocrine system, through various hormones, plays a critical role in regulating when an organism needs to grow and develop. The major endocrine control centre that regulates growth is the pituitary gland, which is a pea-sized organ that lies at the base of the brain. Many genes have been identified that are known to be important in the development of the pituitary gland, and several of these are specific to the cells that make growth hormone (GH). Tumours of the pituitary gland represent the most common intracranial tumour in humans, with 1 in 6 people displaying evidence of these growths at the time of their death. Pituitary tumours, as well as other pituitary abnormalities, can cause disrupted release of many hormones, which consequently affects the quality of life of these patients. We have recently found that companion animals, such as dogs and cats, are known to be susceptible to these pituitary tumours. Growth hormone, one of the major pituitary hormones, is extremely important for the development and growth of an individual, and the release of GH is normally under tight control by the hypothalamus (part of the brain), as well as from other hormones released from tissues such as the liver. Inappropriately high or low GH release can cause a series of disorders, ranging from developmental abnormalities in infants, to dwarfism or metabolic complications in adults, and even an increased risk of certain types of colon cancer. We have recently discovered that another hormone found in the pituitary gland, C-type natriuretic peptide (CNP), is produced very early on in the development of human, mice and fish pituitaries. Our recent investigation of 30 human pituitary adenomas found that each one of these tumours expressed CNP, and the receptor that controls its effects, called GC-B. In addition, our preliminary studies have shown that treating pituitary cells with CNP can cause a dramatic increase in the amount of GH that is made. The work we propose to perform, detailed within this application, will extend our understanding of how CNP might influence the way in which the pituitary gland develops and functions normally. We shall use five different models to examine the effects of CNP; cultured pituitary cells, mice that specifically lack CNP in their pituitary glands, human and cat pituitary tumours and the highly versatile Zebrafish, in which we will silence the genes that encode CNP and establish the consequences for normal growth. In addition, our laboratory is equipped with an extremely efficient genetic analyser, that allows us to measure the amounts of up to 15 different genes in a single sample, greatly increasing our productivity from these very small amounts of tissue. These studies may reveal a role for CNP in the treatment of growth disorders, either as a way to increase GH release in individuals with impaired growth, or by developing drugs to block the effects of CNP and, therefore, reduce GH release. Such findings could lead to an improved quality of life, and a reduced susceptibility to subsequent endocrine disease.