CRH/VP/GLUCOCORTICOID RECEPTOR MRNA REGULATION

CRH/VP/糖皮质激素受体 mRNA 调节

• 批准号: 2883441
• 负责人: DANIEL J. HAISENLEDER
• 金额: $ 7.54万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2883441
• 关键词: RNase protection assay; adrenocorticotropic hormone; corticosteroid receptors; corticosterone; corticotropin releasing factor; dosage; gamma aminobutyrate; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; laboratory rat; messenger RNA; newborn animals; norepinephrine; physiologic stressor; receptor expression; stress; tissue /cell culture; vasopressins

DESCRIPTION (Adapted from applicant's abstract): This application will investigate the role of input signal pattern on CRH and VP gene expression during stress in the rat. Also, to determine if alterations in glucocorticoid receptor (GR) expression within CRH neurons play a role in reduced glucocorticoid negative feedback during stress, GR mRNA and GR cell content will be measured. The hypothesis that will be tested is that altering the signal pattern of both stimulatory (NE, CRH) and inhibitory (corticosterone, GABA) input signals to the CRH neuron play a central role in the induction of VS expression within CRH neurons and maximizing CRH/VP responses (i.e., increases in gene expression and secretion) to stress. These studies will use hypothalamic neurons from neonatal rats as the in vitro model and administer pulsatile (at varying intervals and amplitudes) vs continuous stimuli within a perfusion system. This experimental approach is unique. Not only will effects of stimulatory/inhibitory factors to CRH neurons be examined in a controlled in vitro paradigm one molecule at a time, but the role played by the stimulus pattern for each molecule will also be investigated. During acute or chronic immunobilization stress, the HPA axis plays a critical role in the initiation and maintenance of physiological responses (e.g., metabolic, cardiovascular). The primary hypothalamic component of the HPA is the CRH neuron of the PVN. Of note, during stress VP expression is induced within CRH neurons and plays an important role in potentiating adrenocorticotropic hormone (ACTH) responses to CRH. Data reveal that CRH and VP are released in a pulsatile manner, stimulating similar secretory patterns of both ACTH and glycocorticoids. Stress stimulates a rise in the amplitude and/or frequency of CRH and VP pulsatile secretion, CRH and VP mRNA levels, as well as a reduction in glucocorticoid negative feedback at the PVN. Thus, stress is a unique physiological state in that the CRH/VP neuron is maximally stimulated in the presence of elevated glucocorticoid levels. In humans, alterations in HPA function are noted during aging, depression and Alzheimer's disease and is also an important modulator of the immune system. Therefore, increasing our understanding of the mechanisms that regulate the primary activation site of the system, the CRH/VP neuron, may have implications for various disease states, including AIDS and cancer.

描述（改编自申请人摘要）：本申请将 研究输入信号模式对CRH和VP基因表达的作用 在老鼠的压力下。 此外，为了确定是否改变 CRH神经元内的糖皮质激素受体（GR）表达在 减少应激过程中糖皮质激素的负反馈，减少GR mRNA和GR细胞 内容将被测量。 将要检验的假设是， 改变刺激性（NE，CRH）和抑制性（NE，CRH）的信号模式 （皮质酮，GABA）输入信号CRH神经元起着核心作用 在CRH神经元内诱导VS表达并使CRH/VP最大化 响应（即，基因表达和分泌的增加）。 这些研究将使用新生大鼠的下丘脑神经元作为研究对象。 体外模型和给药脉动（以不同的间隔和幅度） 与灌注系统内的连续刺激相比。 这种实验方法 是独一无二的. CRH的刺激/抑制因子不仅对CRH的功能有影响， 在受控的体外范例中检查神经元， 时间，但刺激模式对每个分子所起的作用将 也要加以研究。 在急性或慢性免疫应激过程中，HPA轴发挥重要作用， 在启动和维持生理反应中的关键作用 (e.g.,代谢、心血管）。 下丘脑的主要成分 HPA是PVN的CRH神经元。 值得注意的是，在应力VP表达期间 在CRH神经元内被诱导，并在增强 促肾上腺皮质激素（ACTH）对CRH的反应。 数据显示， 和VP以脉冲方式释放，刺激类似的分泌 ACTH和糖皮质激素的模式。 压力刺激了 CRH和VP脉冲分泌的幅度和/或频率， mRNA水平，以及糖皮质激素负反馈的减少， PVN。 因此，应激是一种独特的生理状态，因为CRH/VP 在糖皮质激素升高的情况下，神经元受到最大刺激 程度. 在人类中，HPA功能的改变在衰老过程中被注意到， 抑郁症和阿尔茨海默病，也是一个重要的调制器， 免疫系统 因此，增加我们对这些机制的了解， 调节该系统的主要激活位点，CRH/VP神经元， 可能对各种疾病状态有影响，包括艾滋病和癌症。