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

生长激素发育的调节

• 批准号: BB/L002795/1
• 负责人: Robert Fowkes
• 金额: $ 43.17万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL002795%2F1
• 关键词: Regulation; somatotroph; development; function; type

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.

生物体的生长是体内平衡的主要组成部分之一。因此，适当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起着关键作用。调节生长的主要内分泌控制中心是脑下垂体，它是位于大脑底部的豌豆大小的器官。许多基因已被确定是已知的重要在脑垂体的发展，其中几个是特定的细胞，使生长激素（GH）。脑下垂体肿瘤是人类最常见的颅内肿瘤，每6个人中就有1人在死亡时显示出这些生长的证据。垂体瘤以及其他垂体异常可导致许多激素的释放中断，从而影响这些患者的生活质量。我们最近发现，伴侣动物，如狗和猫，已知易患这些垂体瘤。生长激素是一种主要的脑垂体激素，对个体的发育和生长非常重要，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。不适当的高或低GH释放可导致一系列疾病，从婴儿的发育异常到成人的侏儒症或代谢并发症，甚至增加某些类型结肠癌的风险。我们最近发现，在脑垂体中发现的另一种激素，C型利钠肽（CNP），在人类，小鼠和鱼类脑垂体发育的早期就产生了。我们最近对30个人垂体腺瘤的研究发现，这些肿瘤中的每一个都表达CNP，以及控制其作用的受体，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的产生量急剧增加。我们建议执行的工作（在本申请中详述）将扩展我们对CNP如何影响脑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检查CNP的影响;培养的垂体细胞，垂体腺中特别缺乏CNP的小鼠，人类和猫垂体肿瘤以及高度通用的斑马鱼，我们将沉默编码CNP的基因并建立正常生长的后果。此外，我们的实验室还配备了一台非常高效的基因分析仪，使我们能够测量单个样本中多达15种不同基因的数量，大大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在治疗生长障碍中的作用，无论是作为一种增加生长受损个体GH释放的方法，还是通过开发药物来阻断CNP的作用，从而减少GH释放。这些发现可能会改善生活质量，降低对随后内分泌疾病的易感性。

项目成果

Spatial expression profiling reveals tissue-specific sexual dimorphism of the natriuretic peptide system in mice

空间表达谱揭示小鼠利钠肽系统的组织特异性性别二态性

• DOI: 10.1530/endoabs.34.p156
• 发表时间: 2014
• 期刊: Endocrine Abstracts
• 作者: Mirczuk S

Expression Profiling of the Natriuretic Peptide System in Endocrine Tissues of Mice and Cats

小鼠和猫内分泌组织中利尿钠肽系统的表达谱

• 发表时间: 2014
• 期刊: Endocrine Reviews
• 影响因子: 20.3
• 作者: Mirczuk SM

Pharmacological and Genetic Disruption of C-Type Natriuretic Peptide (nppcl) Expression in Zebrafish (Danio rerio) Causes Stunted Growth during Development.

• DOI: 10.3390/ijms241612921
• 发表时间: 2023-08-18
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Lessey, Andrew J.;Mirczuk, Samantha M.;Chand, Annisa N.;Kurrasch, Deborah M.;Korbonits, Marta;Niessen, Stijn J. M.;Mcardle, Craig A.;Mcgonnell, Imelda M.;Fowkes, Robert C.
• 通讯作者: Fowkes, Robert C.

C-Type Natriuretic Peptide Regulates Growth and Pituitary Development in Embryonic Zebrafish (Danio rerio)

C 型利钠肽调节胚胎斑马鱼（斑马鱼）的生长和垂体发育

• 发表时间: 2014
• 期刊: Endocrine Reviews
• 影响因子: 20.3
• 作者: Lessey AJ

C-type natriuretic peptide regulates growth and pituitary development in the zebrafish (Danio rerio)

C 型利钠肽调节斑马鱼（斑马鱼）的生长和垂体发育

• DOI: 10.1530/endoabs.34.p163
• 发表时间: 2014
• 期刊: Endocrine Abstracts
• 作者: Lessey A