Sympathetic Ganglia: New Target for ACTH with Stress

描述(由申请人提供)：交感神经系统的激活和去甲肾上腺素(NE)的升高与几种常见的心血管疾病有关，包括心力衰竭。我们的初步结果表明，促肾上腺皮质激素(ACTH)在交感神经系统的调节中起着关键作用，特别是在应激期间。他们还提示ACTH可能直接作用于交感神经节，激活NE生物合成酶的基因表达。如果被证明是正确的，这将是ACTH的一个新的作用，并可能对进一步了解NE与严重心血管疾病的关系至关重要。我们认为，ACTH触发了交感神经元中cAMP介导的NE生物合成酶(TH和DBH)的转录激活。具体目标是： 目的1：测定每日单次或多次注射不同浓度ACTH后，血浆ACTH、皮质酮、去甲肾上腺素和血压变化的时程。将这些变化与对压力的反应进行比较。 目的：验证ACTH在大鼠交感神经元上调ACTH受体(MC2R)水平并触发cAMP介导的NE生物合成酶基因转录激活的假说。 目的：验证ACTH在应激状态下直接影响交感神经节NE生物合成系统激活的假说，该作用不依赖于肾上腺糖皮质激素的升高。 目的：验证ACTH与交感神经节的功能性结合，并确定在基础条件下或给予ACTH后是否存在其他ACTH反应性受体(除MC2R外)的表达。 目的：探讨促肾上腺皮质激素信号转导机制(S)对培养的颈上神经节细胞神经递质相关基因表达的影响。验证ACTH触发交感神经元cAMP介导的TH和DBH基因转录激活的假说 这项研究的发现将表明ACTH的一个新的作用，并将为应激影响心血管系统的机制提供新的见解。此外，它还可能基于ACTH受体拮抗剂，为治疗充血性心力衰竭和其他情况(如衰老)提供一种全新的治疗方法，这些情况显示出交感神经活性升高。

DESCRIPTION (provided by applicant): The activation of the sympathetic nervous system and elevation of norepinephrine (NE) are associated with several prevalent cardiovascular disorders including heart failure. Our preliminary results suggest that ACTH (adrenocorticotropic hormone) plays a crucial role in the regulation of the sympathetic nervous system, especially during stress. They also suggest that ACTH may act directly on sympathetic ganglia to activate gene expression of NE biosynthetic enzymes. If proven correct, this would be a novel role for ACTH and may be crucial in further understanding the relationship of NE and serious cardiovascular disorders. We propose that ACTH triggers cAMP mediated transcriptional activation of the NE biosynthetic enzymes (TH and DBH) in sympathetic neurons. The specific aims are: Aim 1: Determine the time course for alterations in plasma ACTH, corticosterone, NE and blood pressure in response to single or repeated daily injections of several concentrations of ACTH. Compare these changes with response to stress. Aim 2: Test the hypothesis that in rat sympathetic neurons ACTH up-regulates levels of the ACTH receptor (MC2R) and triggers cAMP mediated transcriptional activation of the genes encoding NE biosynthetic enzymes. Aim 3: Test the hypothesis that with stress ACTH has a direct effect on activation of the NE biosynthetic system in sympathetic ganglia independent of its elevation of adrenal glucocorticoids. Aim 4: Validate functional ACTH binding to sympathetic ganglia and determine whether there are other ACTH responsive receptors (besides MC2R) that are expressed under basal conditions or following administration of ACTH. Aim 5: Determine the ACTH signaling mechanism(s) leading to changes in neurotransmitter related gene expression in superior cervical ganglia cell cultures. Test the hypothesis that ACTH triggers cAMP mediated transcriptional activation of the genes encoding TH and DBH in sympathetic neurons The findings of this study would indicate a novel role for ACTH, and will provide new insight into the mechanism by which stress affects the cardiovascular system. Moreover, it might enable a completely new therapeutic approach to treatment of congestive heart failure and other situations, such as aging, which display elevate sympathetic activity, based on ACTH receptor antagonists.