Creation of a mouse model of isolated GH deficiency

孤立性 GH 缺乏症小鼠模型的创建

• 批准号: 7267932
• 负责人: Roberto Salvatori
• 金额: $ 23.89万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267932
• 关键词: Ablation; Acute; American; Animal Model; Animals; Biochemical; Caring; Cell Proliferation; Cells; Child; Childhood; Clinical; Condition; Daily; Development; Endocrinologist; Failure; Functional disorder; Genes; Growth; Half-Life; Height; Hormones; Human; Hypothalamic structure; Image; Injection of therapeutic agent; JI-38; Knock-out; Life; Magnetic Resonance Imaging; Measurement; Modeling; Mus; Numbers; Pituitary Gland; Pituitary Hormones; Pituitary Hypoplasia; Production; Public Health; Recombinants; Somatotropin; Somatotropin-Releasing Hormone; Stimulus; Technology; Testing; Therapeutic; Thinking; United States Food and Drug Administration; analog; base; cost; ghrelin; growth hormone deficiency; hormone analog; hormone deficiency; mouse model; pediatrician; postnatal; r-hGH-M; response; tool

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 分泌缺失或减少（孤立性 GH 缺乏症，IGHD）会导致儿童生长障碍。大多数 IGHD 病例是特发性的，是由于 GHRH 缺乏或失调所致，而不是由于生长激素细胞异常。尽管大多数 IGHD 儿童的生长会对 GHRH 产生反应，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。对于没有 GHD（特发性身材矮小，ISS）生化证据的身材矮小儿童，同样的疗法可以增加最终身高。基于这一观察结果，hGH 疗法最近已获得 FDA 批准用于患有严重 ISS（身高<1%）的儿童，使适合接受 hGH 治疗的美国儿童人数增加到 410,000 人，每年的费用为 80 亿美元。因此，需要比 hGH 更便宜的疗法，或者可以更低频率甚至口服给药的疗法。此类疗法的目的应该是在缺乏 GHRH 的情况下直接增加垂体产生内源性 GH。潜在的治疗候选者是生长素释放肽类似物（GH 促分泌素，GHS1）或长效 GHRH 类似物。尽管存在几种 GHD 小鼠模型，但没有一种适合测试此类疗法，因为它们不能响应外源刺激而产生 GH。理想的动物模型应缺乏 GHRH，并且生长激素细胞具有正常的发育和功能。我们开发了一种 GHRH 基因（GHRHKO）全面消除（敲除，KO）的小鼠。 GHRHKO 小鼠患有 GHD，但也有严重的生长激素细胞发育不全，这限制了它们用于测试潜在的 IGHD 疗法。虽然生长发育不全可以通过 GHRH 治疗逆转，但这种逆转只是部分的。因此，我们建议创建一种具有暂时条件性去除 GHRH 基因的小鼠。我们预测这只小鼠将具有正常的生长激素细胞发育，并具有出生后获得的 IGHD。该模型将使我们能够确定 GHS 是否对生长激素细胞有显着的直接影响。此外，它将模拟大多数 IGHD 儿童发生的临床情况，并且将成为研究旨在增加内源性 GH 分泌的疗法效果的重要工具。