CENTRAL REGULATION OF ADRENOCORTICOTROPIN SECRETION

肾上腺皮质激素分泌的中央调节

• 批准号: 3231469
• 负责人: PAUL M PLOTSKY
• 金额: $ 14.01万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1995-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3231469
• 关键词: adrenalectomy; adrenergic receptor; adrenocorticotropic hormone; catecholamines; circadian rhythms; corticosterone; corticotropin releasing factor; denervation; developmental neurobiology; electrochemistry; experimental brain lesion; gene expression; high performance liquid chromatography; hormone regulation /control mechanism; hypothalamic pituitary axis; hypothalamus; immunocytochemistry; in situ hybridization; inhibin; laboratory rat; microdialysis; neuroendocrine system; neuropharmacology; norepinephrine; paraventricular nucleus; pituitary adrenal axis; protooncogene; radioimmunoassay; receptor expression; reserpine; secretion; stressor

Corticotropin releasing factor (CRF-4l)-producing perikarya in the hypothalamic parvocellular paraventricular nuclei (pPVN) play an integral role in regulation of adenohypophysial adrenocorticotropin (ACTH) secretion, pro-opiomelanocortin (POMC) gene expression and, thus, in the regulation of adrenocortical secretion. The secretory activity of CRF-positive neurons is modulated by humoral factors (glucocorticoids, glucose, etc) and by numerous afferent fibers conveying information about interoceptive and exteroceptive stimuli. CRF-41 neurons receive heavy innervation from medullary cell groups which, themselves, receive a diverse array of visceral and somatosensory inputs. Therefore they are excellent candidates for mediating activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to a number of visceral (e.g. hypovolemia, hypotension) and somatic (e.g. pain) stimuli. Efferents from medullary regions are the major source of inputs containing norepinephrine (NE), epinephrine (EPI), neuropeptide Y (NPY), and a peptide with activin-like immunoreactivity (IbetaA-LI) to the CRF-rich pPVN. These putative transmitters generally facilitate CRF-41 secretion, although the nature of adrenergic receptor subtypes mediating catecholamine actions remain controversial. Ultimately, mechanisms must exist to ensure coordination of gene expression and secretion. In the present proposal, we will test the hypothesis that, individually or in combination, NE and IbetaA-LI (a member of the TGF-beta growth factor family) participate in the coordination of CRF-41 secretion and gene expression. Because of the biochemical diversity of these transmitters and the likelihood that their release occurs in a specific manner dependent upon the stimulus characteristics (modality, amplitude, frequency, duration), we hypothesize that these transmitters differentially affect secretion and gene expression in the target cells via multiple intracellular pathways. Neurotransmitter release evokes both rapid and slow responses in neurons, thus permitting an immediate response to the stimulus as well as longer-term adaptive plasticity. It has been suggested that induction of the c-fos gene, which encodes a nuclear phosphoprotein with DNA binding properties consistent that of a transcriptional regulator, is a component of the signaling cascade by which specific transmitters may modulate neuronal gene expression. Therefore, we will evaluate whether any of these neurotransmitters activate the c-fos gene and then determine whether or not C-fos activation is correlated with CRF-41 secretion and/or gene expression.

皮质激素释放因子（CRF-4L） - 产生周期性 下丘脑旁脑室室核核（PPVN）的表现不佳 在调节腺型型肾上腺皮质激素（ACTH）中的作用 分泌，促蛋白聚糖素（POMC）基因表达，因此在 肾上腺皮质分泌的调节。 分泌活动 CRF阳性神经元受体液因子（糖皮质激素， 葡萄糖等）以及许多传入纤维传达有关的信息 互感和外部感受性刺激。 CRF-41神经元沉重 髓质细胞组的神经支配本身都接受 各种各样的内脏和体感输入。 因此它们是 出色的候选者用于中介激活 下丘脑 - 垂体 - 肾上腺（HPA）轴响应许多 内脏（例如低血症，低血压）和躯体（例如疼痛）刺激。 髓质区域的传出是投入的主要来源 含有去甲肾上腺素（NE），肾上腺素（EPI），神经肽Y（NPY）， 以及具有激活素样免疫反应性（Ibetaa-li）的肽 富含CRF的PPVN。 这些推定的发射器通常促进CRF-41 分泌，尽管肾上腺素受体亚型的性质介导 儿茶酚胺的作用仍然存在争议。 最终，机制必须 存在以确保基因表达和分泌的协调。 在 目前的建议，我们将测试以下假设 组合NE和IBETAA-LI（TGF-β生长因子的成员 家庭）参与CRF-41分泌和基因的协调 表达。 由于这些发射机的生化多样性 以及它们以特定方式释放的可能性 取决于刺激特征（振幅，振幅， 频率，持续时间），我们假设这些发射器 差异影响靶细胞中的分泌和基因表达 通过多个细胞内途径。 神经递质释放唤起 神经元的快速反应和缓慢反应，因此可以立即 对刺激以及长期自适应可塑性的反应。 它 已经提出了c-fos基因的诱导，该基因编码A 具有DNA结合特性一致的核磷酸蛋白 转录调节器是信号级联的组成部分 哪些特定发射器可能会调节神经元基因表达。 因此，我们将评估这些神经递质中的任何一个 激活C-FOS基因，然后确定是否c-fos 激活与CRF-41分泌和/或基因表达相关。