GROWTH REGULATION OF THE NEUROBIOLOGY OF PUBERTY

尽管许多物种的研究表明，促性腺激素释放激素(GnRH)神经元的神经化学输入发生结构或功能上的变化，导致GnRH分泌在青春期开始发育增加，但导致这种变化的因素(S)尚不清楚。这个项目将利用雌性恒河猴来检验这样的假设，即生长过程中发出的信号，即胰岛素样生长因子-I，改变了这种输入的性质，增加了GnRH和脑下垂体促性腺激素的分泌，启动了青春期。工作假设是，青春期前IGF-I的增加刺激了GnRH分泌的出现，这是通过夜间脉动性促性腺激素释放来评估的。《特定目标1》将使用两种不同的生长激素不敏感模型来检验这一假说。用生长激素受体拮抗剂处理幼鼠，可建立生长激素-胰岛素样生长因子-I缺乏模型。据预测，与对照组相比，接受GH拮抗剂治疗的女性夜间促性腺激素分泌将受到干扰，但IGF-I替代治疗将使这一模式正常化。在第二项研究中，通过用促性腺激素释放激素类似物来延长性腺激素低下的青春期前时期，将阻止幼虫的生殖成熟。当对照雌性在相当于青春期中期的年龄停止类似物治疗时，预测与仅使用类似物治疗的雌性相比，与仅使用类似物治疗的雌性相比，与GH受体拮抗剂联合治疗将抑制GnRH脉冲发生器的表达，该脉冲发生器是从强健的夜间促性腺激素脉冲推断的。相反，GH拮抗对GnRH脉冲发生器的这种抑制作用将被IGF-I联合应用逆转。具体目标2将检验这一假设，即在新生儿期GH-IGF-I轴的完整性对于随后的GH-IGF-I活动、青春期前生长和青春期的时间至关重要。接受新生儿治疗的女性(从出生起--8个月)使用GH受体拮抗剂的患者将与对照组和接受GnRH类似物治疗的新生儿女性进行比较，这种治疗方法已知可以延缓猴子和大鼠的青春期。据预测，出生后GH-IGF-I的干扰将导致GH轴的长期缺陷，减少生长，延迟促性腺激素的分泌和青春期的开始。来自这些研究的数据将为生长激素轴如何调节青春期提供重要的新信息，从而更好地理解儿童生长发育中的异常。

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.