Creation of a mouse model of isolated GH deficiency

单纯 GH 缺乏症小鼠模型的创建

• 批准号: 7139523
• 负责人: Roberto Salvatori
• 金额: $ 20.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139523
• 关键词: disease /disorder model; endocrine disorder; genetically modified animals; growth hormone releasing hormone; hormone regulation /control mechanism; laboratory mouse; model design /development; pituitary dwarfism; somatotropin

DESCRIPTION (provided by applicant): Absent or reduced secretion of GH (isolated GH deficiency, IGHD) causes growth failure in children. The majority of IGHD cases is idiopathic, due to lack or deregulation of GHRH rather than to abnormalities in the somatotroph cells. Although most IGHD children grow in response to GHRH, due to GHRH short half-life they are commonly treated with daily injections of human recombinant GH (hGH). The same therapy increases final height in children with short stature who do not have biochemical evidence of GHD (idiopathic short stature, ISS). Based on this observation, hGH therapy has been recently approved by the FDA for children with severe ISS (stature < 1st percentile), increasing the number of American children that are candidates for hGH treatment to 410,000, with a yearly cost of $8 billion. Hence, the need for therapies that are less expensive than hGH, or can be administered less frequently or even orally. Such therapies should be aimed to directly increase the production of endogenous GH by the pituitary in the absence of GHRH. Potential therapeutic candidates are the Ghrelin analogues (GH secretagogues, GHS1), or long-acting GHRH analogues. Although several mouse models of GHD exist, none of them is suitable to test such therapies, as they cannot produce GH in response to exogenous stimuli. An ideal animal model would lack GHRH, and have normal development and function of the somatotroph cells. We have developed a mouse with generalized ablation (knock out, KO) of the GHRH gene (GHRHKO). GHRHKO mice have GHD but also severe somatotroph cells hypoplasia that limits their use to test potential IGHD therapies. Although hypoplasia can be reversed by GHRH treatment, such reversal is only partial. Therefore, we propose the creation of a mouse with temporal conditional ablation of the GHRH gene. We predict that this mouse will have normal somatotroph cell development, with IGHD acquired postnatally. This model will allow us to determine if GHS' have a significant direct effect on the somatotroph cells. In addition, it will mimic the clinical scenario that occurs in most children with IGHD, and it will be an important tool to study the effects of therapies aimed to increase the secretion of endogenous GH.

描述（由申请人提供）：GH分泌缺乏或减少（孤立性GH缺乏症，IGHD）导致儿童生长障碍。大多数IGHD病例是特发性的，由于缺乏或失调的GHRH，而不是异常的生长激素细胞。虽然大多数IGHD儿童生长对GHRH有反应，但由于GHRH半衰期短，他们通常每天注射人重组GH（hGH）进行治疗。相同的治疗增加了没有GHD（特发性身材矮小，ISS）生化证据的身材矮小儿童的最终身高。基于这一观察结果，hGH治疗最近已被FDA批准用于患有严重ISS（身高<第一百分位数）的儿童，将美国儿童作为hGH治疗候选者的数量增加到410，000，每年花费80亿美元。因此，需要比hGH便宜的疗法，或者可以不太频繁地甚至口服施用。这种疗法的目的应该是直接增加生产的内源性生长激素的垂体GHRH的情况下。潜在的治疗候选物是Ghrelin类似物（GH促分泌素，GHS 1）或长效GHRH类似物。虽然存在几种GHD小鼠模型，但它们都不适合测试这种疗法，因为它们不能响应外源性刺激产生GH。理想的动物模型是缺乏GHRH，生长激素细胞发育和功能正常。我们已经开发了一种具有GHRH基因（GHRHKO）的全身性消融（敲除，KO）的小鼠。GHRHKO小鼠患有GHD，但也有严重的促生长细胞发育不全，这限制了它们用于测试潜在的IGHD疗法。尽管GHRH治疗可以逆转发育不全，但这种逆转只是部分的。因此，我们建议建立一个小鼠的GHRH基因的时间条件消融。我们预测，这只小鼠将有正常的生长激素细胞发育，与IGHD后天。这个模型将使我们能够确定GHS是否对生长激素细胞有显著的直接影响。此外，它将模拟大多数IGHD儿童的临床情况，并将成为研究旨在增加内源性GH分泌的治疗效果的重要工具。