CRH/VP/GLUCOCORTICOID RECEPTOR MRNA REGULATION

描述(改编自申请人的摘要)：本申请将 研究输入信号模式对CRH和VP基因表达的影响 在大鼠的应激过程中。此外，要确定是否更改了 糖皮质激素受体(GR)在CRH神经元表达中的作用 应激时糖皮质激素负反馈、GR mRNA和GR细胞减少 内容将被测量。将被检验的假设是 改变刺激性(NE、CRH)和抑制性信号模式 (皮质酮，GABA)传入CRH神经元的信号起着中枢作用。 在诱导CRH神经元内VS表达和最大化CRH/VP中的作用 对压力的反应(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 体外模型和给药脉搏(以不同的间隔和幅度) VS灌流系统内的连续刺激。这种实验性的方法 是独一无二的。不仅刺激/抑制因子对CRH的影响 在受控的体外范例中对神经元进行一次一个分子的检查 时间，但刺激模式对每个分子所起的作用将 也被调查。 在急性或慢性免疫应激期间，HPA轴发挥着 在启动和维持生理反应中的关键作用 (例如，代谢、心血管)。下丘脑的主要成分 HPA是下丘脑室旁核的CRH神经元。值得注意的是，在应激时VP的表达 在CRH神经元中被诱导，并在增强 促肾上腺皮质激素(ACTH)对CRH的反应。数据显示，CRH 和VP以脉动的方式释放，刺激类似的分泌 促肾上腺皮质激素和糖皮质激素的模式。压力会刺激人的心理健康水平上升 CRH和VP脉冲性分泌的幅度和/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，神经元受到最大程度的刺激 级别。在人类中，HPA功能在衰老过程中会发生变化， 抑郁症和阿尔茨海默病，也是一种重要的调节因子 免疫系统。因此，增加我们对这些机制的理解 调节系统的主要激活部位，CRH/VP神经元， 可能对包括艾滋病和癌症在内的各种疾病状态产生影响。

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.