GROWTH REGULATION OF THE NEUROBIOLOGY OF PUBERTY

青春期神经生物学的生长调节

• 批准号: 6526349
• 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/6526349
• 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改变诱导了青春期开始的GnRH分泌的发育性增加，但导致这种变化的因素尚不清楚。利用雌性恒河猴，该项目将测试一个假设，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和垂体促性腺激素的分泌，开始了青春期。工作的假设是，青春期前IGF-I的增加刺激GnRH分泌的出现，从夜间脉动性腺激素释放来评估。Specific Aim 1将通过使用两种不同的生长激素（GH）不敏感模型来检验这一假设。用生长激素受体拮抗剂治疗幼鱼会产生GH- igf - i缺陷模型。据预测，与对照组相比，接受生长激素拮抗剂治疗的女性夜间促性腺激素分泌将被破坏，但用igf - 1替代治疗将使这种模式正常化。在第二项研究中，生殖成熟将通过用GnRH类似物治疗青少年来延长促性腺功能低下的青春期前期而被阻止。在对照组女性中，在相当于青春期中期的年龄停止类似物治疗后，预测与GH受体拮抗剂联合治疗将抑制发育中的GnRH脉冲发生器的表达，这是由促性腺激素夜间强劲脉冲推断的，与仅接受类似物治疗的女性相比。相反，生长激素拮抗剂对GnRH脉冲发生器的抑制将被igf - 1联合施用逆转。特异性目标2将验证以下假设：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。用生长激素受体拮抗剂治疗新生儿（从出生到8个月）的雌性将与对照组和用GnRH类似物治疗新生儿的雌性进行比较，这种治疗已知可以延迟猴子和大鼠的青春期。据预测，出生后GH- igf - 1的破坏将产生GH轴的长期缺陷，减少生长，延迟出现促性腺激素分泌和青春期发病。从这些研究中获得的数据将为GH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的畸变。