BRAIN INSULIN-LIKE GROWTH FACTOR SOMATOMEDIN RECEPTORS

这项研究的长期目标是了解 大脑在调节生长。各种常见的 代谢性疾病，如糖尿病、营养不良和 肥胖，被认为伴随着生长缺陷 与胰岛素样生长因子-I的异常分泌有关 (IGF-I)经肝给药。一个悬而未决的问题是IGF-I是如何抑制 通过大脑中的反馈机制分泌生长激素。 IGF-I通过直接作用于垂体抑制GH的分泌 腺体，但有证据表明这种负反馈起作用 也是在下丘脑水平，在那里它被认为是 刺激生长激素抑制激素生长抑素的释放 (或生长激素释放抑制因子，SRIF)。这一机制 IGF-I在细胞水平对GH分泌的调节作用 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)，提高了 假设：ME中的IGF-I受体调节SRIF的分泌 脑脊液中的垂体部门脉血。建议数 实验旨在调查三个特定的目标 解决这一假设：(1)确定IGF-I受体是否 位于ME内含SRIF的轴突终末； 为了确定ME中的IGF-I受体是否变得更多 (Upregate)伴随代谢状况 通过降低血浆IGF-I水平；(3)确定IGF-I是否调节 ME中的受体改变SRIF释放对IGF-的敏感性 I.用于测量ME中标记IGF-I结合的方法 将进行定量放射自显影(QAR)：(A)显微镜 放射性自显影颗粒密度的定量测定 体内注射标记的IGF-I到血浆中；(B)计算机图像 大鼠脑放射自显影图像在LKB上的分析 薄膜，由体外标记的脑片和标记的 IGF-I。胰岛素样生长因子-I(及其相关多肽，IGF-II)的结合部位 ME和大脑将通过QAR来测量和表征 测定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 结合中的动态平衡变化。验尸官的血将会是 收集的实验旨在测试ME的变化 胰岛素样生长因子-I受体与ME的敏感性增加有关 SRIF释放至血浆IGF-I水平。这些结果将支持 大脑皮层IGF-I与IGF-I受体相互作用的假说 控制SRIF在垂体门静脉血中的释放。

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.