GROWTH REGULATION OF THE NEUROBIOLOGY OF PUBERTY

青春期神经生物学的生长调节

• 批准号: 6197468
• 负责人: MARK E WILSON
• 金额: $ 32.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6197468
• 关键词: Macaca mulatta; animal puberty; cell growth regulation; female; follicle stimulating hormone; gonadotropin releasing factor; gonadotropins; hormone receptor; hormone regulation /control mechanism; inhibitor /antagonist; insulinlike growth factor; juvenile animal; longitudinal animal study; luteinizing hormone; neurobiology; newborn animals; receptor expression; secretion; somatotropin

Although studies from a variety of species indicate that a structural or functional shift in neurochemical input into gonadotropin releasing hormone (GnRH) neurons induces the developmental increase in GnRH secretion initiating puberty, the factor(s) responsible for this change are not known. Using female rhesus monkeys, this project will test the hypothesis that a signal emanating from growth, namely insulin like growth factor (IGF)-I, changes the nature of this input, increasing GnRH and pituitary gonadotropin secretion, initiating puberty. The working hypothesis is that a prepubertal increase in IGF-I stimulates the emergence of GnRH secretion as assessed from nocturnal pulsatile gonadotropin release. Specific Aim 1 will test this hypothesis by using two different models of growth hormone (GH) insensitivity. A GH-IGF-I deficient model will be produced by treating juveniles with a GH receptor antagonist. It is predicted that the emergence of nocturnal gonadotropin secretion will be disrupted in GH antagonist-treated females compared with controls but replacement therapy with IGF-I will normalize this pattern. In the second study, reproductive maturation will be arrested by treating juveniles with an GnRH analog to prolong the prepubertal period of hypogonadotropism. Upon the cessation of analog treatment at an age equivalent to mid puberty in control females, it is predicted that co-treatment with a GH receptor antagonist will suppress the expression of the developing GnRH pulse generator, inferred from robust nocturnal pulses of gonadotropins, compared to females only treated with the analog. In contrast, this suppression of the GnRH pulse generator by GH antagonism will be reversed by co-administration of IGF-I. Specific Aim 2 will test the hypothesis that the integrity of the GH-IGF-I axis during the neonatal period is essential for the subsequent GH-IGF-I activity, prepubertal growth and the timing of puberty. Females treated neonatally (from birth-8 mo.) with a GH receptor antagonist will be compared to controls and to females treated neonatally with a GnRH analog, a treatment known to delay puberty in monkeys and rats. It is predicted that a postnatal disruption of GH-IGF-I will produce long term deficits in the GH axis, diminishing growth, delaying the emergence gonadotropin secretion and the onset on puberty. The data derived from these studies will provide significant new information on how the GH axis regulates puberty and, thus, a better understanding of aberrations in growth and development in children.

尽管来自多种物种的研究表明，进入促性腺激素释放激素（GnRH）神经元的神经化学输入的结构或功能转变诱导了GnRH分泌的发育增加，启动青春期，但导致这种变化的因素尚不清楚。 该项目将使用雌性恒河猴来检验一种假设，即从生长中发出的信号，即胰岛素样生长因子（IGF）-I，改变了这种输入的性质，增加了GnRH和垂体促性腺激素分泌，启动了青春期。 工作假设是青春期前IGF-I的增加刺激GnRH分泌的出现，这是通过夜间脉冲性促性腺激素释放来评估的。 具体目标1将通过使用两种不同的生长激素（GH）不敏感性模型来检验这一假设。 将通过用GH受体拮抗剂处理青少年来产生GH-IGF-I缺陷模型。 据预测，夜间促性腺激素分泌的出现将在GH拮抗剂治疗的女性与对照组相比，中断，但与IGF-I替代治疗将正常化这种模式。 在第二项研究中，将通过用GnRH类似物治疗青少年以延长促性腺激素减退症的青春期前期来阻止生殖成熟。在相当于对照雌性动物青春期中期的年龄停止类似物治疗后，与仅用类似物治疗的雌性动物相比，预测与GH受体拮抗剂联合治疗将抑制发育中GnRH脉冲发生器的表达，这是从促性腺激素的强夜间脉冲推断的。 相比之下，GH拮抗作用对GnRH脉冲发生器的这种抑制将被IGF-I联合给药逆转。 具体目标2将检验以下假设：新生儿期GH-IGF-I轴的完整性对随后的GH-IGF-I活性、青春期前生长和青春期时间至关重要。 经阴道给药的雌性动物（从出生至8个月）将与对照组和接受GnRH类似物（一种已知可延迟猴和大鼠青春期的治疗）腹腔给药的雌性动物进行比较。 据预测，出生后GH-IGF-I的破坏将在GH轴中产生长期缺陷，减少生长，延迟促性腺激素分泌的出现和青春期的开始。来自这些研究的数据将提供关于GH轴如何调节青春期的重要新信息，从而更好地了解儿童生长和发育中的畸变。