Sympathetic Ganglia: New Target for ACTH with Stress

交感神经节：ACTH 与压力的新目标

• 批准号: 7194366
• 负责人: Esther Louise Sabban
• 金额: $ 34.1万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194366
• 关键词: Adenylate Cyclase; Adrenal Cortex; Adrenal Glands; Affect; Aging; Binding; Biochemical; Blood Pressure; CREB1 gene; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical; Condition; Congestive Heart Failure; Corticosterone; Corticotropin; Corticotropin Receptors; Cultured Cells; Cyclic AMP; Daily; Disease; Dopamine-beta-monooxygenase; Elderly; Elevation; Enzymes; Exposure to; Ganglia; Gene Activation; Gene Expression; Genes; Glucocorticoids; Heart failure; Hormone Responsive; Hormones; Hypothalamic structure; Immobilization; Injection of therapeutic agent; Lead; Mediating; Melanocortin 2 Receptor; Modeling; Myxoid cyst; Neurons; Neurotransmitters; Norepinephrine; Numbers; Peptides; Physiological; Pituitary Gland; Plasma; Play; Rattus; Regulation; Research Personnel; Role; Signal Pathway; Signal Transduction; Stress; Structure of superior cervical ganglion; Sympathetic Ganglia; Sympathetic Nervous System; System; Testing; Therapeutic Intervention; Time; Tissues; Transcriptional Activation; base; biological adaptation to stress; cardiovascular disorder risk; common cellular transcription factor ATF; ganglion cell; insight; novel; novel therapeutics; pre-clinical; programs; receptor; response

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.

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）的升高与包括心力衰竭在内的几种常见心血管疾病有关。我们的初步结果表明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，特别是在压力下。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。如果证明是正确的，这将是ACTH的一个新作用，可能对进一步了解NE与严重心血管疾病的关系至关重要。我们提出ACTH触发cAMP介导的交感神经元NE生物合成酶（TH和DBH）的转录激活。具体目标是：