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（包括心力衰竭）相关。我们的初步研究结果表明，ACTH（促肾上腺皮质激素）在交感神经系统的调节中起着至关重要的作用，特别是在应激过程中。他们还表明，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，这将是一个新的作用，促肾上腺皮质激素和可能是至关重要的，在进一步了解NE和严重的心血管疾病的关系。我们建议，ACTH触发cAMP介导的NE生物合成酶（TH和DBH）在交感神经元的转录激活。具体目标是： 目标1：测定血浆ACTH、皮质酮、NE和血压对每日单次或重复注射几种浓度ACTH的反应变化的时程。将这些变化与对压力的反应进行比较。 目标二：检验大鼠交感神经元中ACTH上调ACTH受体（MC2R）水平并触发cAMP介导的NE生物合成酶编码基因转录激活的假设。 目标3：检验以下假设：应激时ACTH对交感神经节NE生物合成系统的激活有直接影响，而不依赖于肾上腺糖皮质激素的升高。 目标4：与交感神经节结合的非功能性ACTH，并确定是否存在在基础条件下或在给予ACTH后表达的其他ACTH应答受体（除了MC2R）。 目标5：确定导致上级颈神经节细胞培养物中神经递质相关基因表达变化的ACTH信号传导机制。验证ACTH触发cAMP介导的交感神经元中编码TH和DBH的基因的转录激活的假设 这项研究的发现将表明ACTH的一个新的作用，并将提供新的见解应激影响心血管系统的机制。此外，基于ACTH受体拮抗剂，它可能能够实现治疗充血性心力衰竭和其他情况（例如衰老）的全新治疗方法，这些情况显示交感神经活性升高。

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.