Creation of a mouse model of isolated GH deficiency

描述（由申请人提供）：生长激素分泌不足或减少（孤立性生长激素缺乏症，IGHD）导致儿童生长衰竭。大多数IGHD病例是特发性的，由于GHRH缺乏或失调，而不是由于生长发育不良细胞的异常。虽然大多数IGHD儿童对GHRH有反应，但由于GHRH的半衰期短，他们通常每天注射人重组GH （hGH）进行治疗。同样的治疗可以增加没有GHD生化证据的矮小儿童的最终身高（特发性矮小，ISS）。基于这一观察，hGH治疗最近已被FDA批准用于重度ISS（身高<第一百分位）儿童，使候选hGH治疗的美国儿童数量增加到41万，每年花费80亿美元。因此，需要比生长激素更便宜的治疗方法，或者可以不那么频繁地使用，甚至口服。这种治疗的目的应该是在缺乏GHRH的情况下，通过垂体直接增加内源性GH的产生。潜在的治疗候选人是Ghrelin类似物（GH分泌物，GHS1），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，因为它们不能对外源刺激产生生长激素。理想的动物模型应该是缺乏GHRH，生长营养细胞发育正常，功能正常。我们开发了一种具有GHRH基因（GHRHKO）全面性消融（敲除，KO）的小鼠。GHRHKO小鼠有GHD，但也有严重的生长不良细胞发育不良，这限制了它们用于测试潜在的IGHD治疗方法。虽然发育不良可以通过GHRH治疗逆转，但这种逆转只是部分的。因此，我们提出创建一个小鼠与时间条件消融GHRH基因。我们预测这只小鼠将具有正常的生长缺陷细胞发育，并在出生后获得IGHD。该模型将使我们能够确定GHS是否对生长缺陷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。

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.