OSMOTIC MODULATION OF HYPOTHALAMIC STEROID FEEDBACK

下丘脑类固醇反馈的渗透调节

• 批准号: 2628912
• 负责人: THOMAS G SHERMAN
• 金额: $ 19.24万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-20 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2628912
• 关键词: GABA receptor; afferent nerve; arginine vasopressin; autoradiography; biofeedback; cAMP response element binding protein; corticosteroid receptors; gene induction /repression; gene targeting; genetic transcription; genetically modified animals; glucocorticoids; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; immunocytochemistry; laboratory mouse; laboratory rat; neuropeptides; osmotic pressure; radioimmunoassay; receptor expression; statistics /biometry

The studies described in this revised proposal investigate the functional implications and the mechanistic underpinnings of a novel form of glucocorticoid feedback regulation in the hypothalamo- neurohypophyseal system. We have identified a neuroendocrine paradigm in which negative glucocorticoid feedback on vasopressin expression is established by cell-type specific, de novo, induction of glucocorticoid receptors during hypoosmolality. Magnocellular vasopressin gene expression is generally insensitive to circulating glucocorticoid levels, and this insensitivity can be ascribed to the absence of glucocorticoid receptors in magnocelluar vasopressin neurons. With the establishment of hypoosmolality (plasma osmolality less than 275 mEq/liter), however, the complete inhibition of vasopressin transcription and the first-order decay of cytoplasmic vasopressin mRNA levels is accompanied by the induction of glucocorticoid receptor expression. In the hypoosmolar rat, the inhibition of adrenal steroid synthesis, the antagonism of glucocorticoid receptors with RU486, or adrenalectomy, all result in the re-establishment of basal vasopressin transcriptional activity; thus, the induction of glucocorticoid receptor expression in magnocellular vasopressin neurons represents a novel form of physiologically-specific feedback control that has a significant impact on central nervous system models of hormone regulated feedback in general, on proposed mechanisms of vasopressin regulation in particular, and possibly on the clinical management of patients with hypoosmolality and adrenal insufficiency. Within Aim 1, studies propose to examine the synaptic pharmacology and osmotic afferent pathways involved in the hypoosmolar induction of glucocorticoid receptor expression. We will also examine the temporal association of magnocellular phosphoCREB (pCREB) and CREMalpha expression in this process. In addition, we propose to test the functional role of pCREB in this process by utilizing mice deficient in CREB expression via gene targeting. Within Aim 2, studies propose to study the physiological significance of this novel glucocorticoid feedback system on neurohypophyseal vasopressin expression, and to investigate the apparent uncoupling of vasopressin transcription and secretion under hypoosmolar conditions and/or adrenal insufficiency. Finally, we will examine the new hypothalamic peptide, orphanin FQ, and the magnocellular expression of its receptor, LC132, as negative regulators of magnocellular function during hypoosmolality.

本修订提案中描述的研究调查了 小说的功能含义和机制基础 下丘脑中糖皮质激素反馈调节的形式 神经垂体系统。 我们已经确定了一个神经内分泌范式 其中糖皮质激素对加压素表达的负反馈是 通过细胞类型特异性、从头诱导糖皮质激素建立 低渗透压期间的受体。 大细胞加压素基因 表达通常对循环糖皮质激素不敏感 水平，这种不敏感可以归因于缺乏 大细胞加压素神经元中的糖皮质激素受体。随着 建立低渗透压（血浆渗透压低于 275 mEq/升），然而，加压素的完全抑制 细胞质加压素 mRNA 的转录和一级衰减 水平伴随着糖皮质激素受体的诱导 表达。 在低渗大鼠中，肾上腺类固醇的抑制作用 合成、RU486对糖皮质激素受体的拮抗作用，或 肾上腺切除术，所有这些都会导致基础加压素的重建 转录活性；因此，糖皮质激素受体的诱导 大细胞加压素神经元的表达代表了一种新形式 生理特异性反馈控制具有显着的 激素调节反馈对中枢神经系统模型的影响 总的来说，关于加压素调节的拟议机制 特别是，并且可能与患有以下疾病的患者的临床管理有关： 低渗透压和肾上腺皮质功能不全。 在目标 1 中，研究提出 检查突触药理学和渗透传入途径 参与糖皮质激素受体的低渗诱导 表达。 我们还将检查时间关联 巨细胞磷酸化 CREB ​​(pCREB) 和 CREMalpha 表达 过程。 此外，我们建议测试 pCREB ​​的功能作用 在此过程中，通过基因利用 CREB ​​表达缺陷的小鼠 瞄准。 在目标 2 中，研究建议研究生理学 这种新型糖皮质激素反馈系统的意义 神经垂体加压素的表达，并调查表观 低渗条件下加压素转录和分泌的解偶联 条件和/或肾上腺功能不全。 最后，我们将检查 新的下丘脑肽、孤啡肽FQ和巨细胞表达 其受体 LC132 作为大细胞功能的负调节因子 低渗透压期间。