BRAIN INSULIN-LIKE GROWTH FACTOR SOMATOMEDIN RECEPTORS

这项研究的长期目标是了解 大脑对生长的调节作用。 各种常见 代谢紊乱，如糖尿病、营养不良，以及 肥胖，伴随着生长缺陷， 与胰岛素样生长因子-I分泌异常有关 （IGF-I）的肝脏。 一个未解决的问题是IGF-I如何抑制 通过大脑中的反馈机制分泌GH。 IGF-I通过直接作用于垂体抑制GH分泌 腺，但证据表明，这种负反馈运作， 下丘脑水平也是如此， 刺激生长激素抑制激素生长抑素的释放 (or生长激素释放抑制因子（SRIF）。 机制 在IGF-I水平参与GH分泌的调节， 然而，大脑是未知的。 最近的数据表明IGF-I 受体存在于正中隆起（ME）， 假设：ME中的IGF-I受体调节SRIF分泌， 垂体门静脉血在ME。建议 实验旨在研究三个具体目标， 解决这一假设：（1）为了确定IGF-I受体是否 位于ME内含有SRIF的轴突末端;（2） 为了确定ME中的IGF-I受体是否变得更多， （上调）与代谢条件伴随 （3）确定IGF-I的调节是否与胰岛素样生长因子（IGF-1）的水平有关。 ME中的受体改变了SRIF释放对IGF-1的敏感性。 I. 用于测量ME中标记IGF-I结合的方法 定量放射自显影（QAR）：（a）显微镜 定量放射自显影颗粒密度在ME后， 将标记的IGF-I体内注射到血浆中;（B）计算机图像 大鼠脑放射自显影LKB图像分析 膜，通过体外标记脑切片产生， IGF-I。 IGF-I（和相关肽，IGF-II）在 ME和大脑将通过QAR进行测量和表征， 确定IGF类似物的特异性并验证受体 状态，并确定ME IGF-I受体是否经历 结合中的稳态变化。 法医的血 收集的实验旨在测试ME的变化是否 IGF-I受体与ME敏感性增加相关 SRIF释放至血浆IGF-I水平。 这些结果将支持 在ME中IGF-I与IGF-I受体相互作用的假设 以控制SRIF释放到垂体门静脉血中。

The long range goal of this research is to understand the role of the brain in the regulation of growth. A variety of common metablic disorders, such as diabetes mellitus, malnutrition, and obesity, are accompanied by growth deficiencies thought to be associated with abnormal secretion of insulin-like growth factor-I (IGF-I) by the liver. An unsolved problem is how IGF-I inhibits the secretion of GH by a feedback mechanism operating in the brain. IGF-I inhibits GH secretion by acting directly on the pituitary gland, but evidence indicates that this negative feedback operates also at the level of the hypothalamus, where it is thought to stimulate the release of the GH inhibitory hormone, somatostatin (or somatotropin release inhibitory factor, SRIF). The mechanism involved in the regulation of GH secretion by IGF-I at the level of the brain is unknown, however. Recent data indicating that IGF-I receptors are present in the median eminence (ME) raises the hypothesis: IGF-I receptors inthe ME regulate SRIF secretion into the hypophyseal portal blood in the ME. The proposed experiments are designed to investigate three specific aims that address this hypothesis: (1) To determine if IGF-I receptors are located on the terminals of axons containing SRIF in the ME; (2) To determine if IGF-I receptors in the ME become more numerous (upregulate) in association with metabolic conditions accompanied by low plasma IGF-I levels; (3) To determine if regulation of IGF-I receptors in the ME changes the senitivity of SRIF release to IGF- I. The method used to measure binding of labeled IGF-I in the ME will be quantitative autoradiography (QAR): (a) microscopic quantitation of autoradiographic grain density in the ME after in vivo injection of labeled IGF-I into plasma; (b) computer image analysis of autoradiographic images of rat brain images on LKB film, produced by in vitro labeling of brain slices with labeled IGF-I. Binding sites for IGF-I (and the related peptide, IGF-II) in the ME and brain will be measured and characterized by QAR to determine specficity for IGF's analogues and verify receptor status, and to determine if ME IGF-I receptors undergo homeostatic changes in binding. Blood from the ME will be collected in experiments designed to test whether changes in ME IGF-I receptors are associated with increased sensitivity of ME SRIF release to plasma IGF-I levels. These results will support the hypothesis that IGF-I interacts with IGF-I receptors in the ME to control the release of SRIF into hypophyseal portal blood.