Sympathetic Ganglia: New Target for ACTH with Stress

交感神经节：ACTH 与压力的新目标

基本信息

批准号：
7393071
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
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7393071
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

项目摘要

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流行的心血管疾病有关。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发挥着至关重要的作用，尤其是在压力期间。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 ACTH 的一个新作用，并且对于进一步了解 NE 和严重心血管疾病的关系可能至关重要。我们认为 ACTH 触发交感神经元中 NE 生物合成酶（TH 和 DBH）的 cAMP 介导的转录激活。具体目标是：目标 1：确定每日单次或重复注射几种浓度的 ACTH 后血浆 ACTH、皮质酮、NE 和血压变化的时间过程。将这些变化与对压力的反应进行比较。目标 2：测试大鼠交感神经元中 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，与肾上腺糖皮质激素的升高无关。目标 4：验证 ACTH 与交感神经节的功能性结合，并确定是否存在在基础条件下或给予 ACTH 后表达的其他 ACTH 反应性受体（除 MC2R 外）。目标 5：确定导致颈上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。检验 ACTH 触发交感神经元中 cAMP 介导的 TH 和 DBH 编码基因转录激活的假设这项研究的结果将表明 ACTH 的新作用，并将为压力影响心血管系统的机制提供新的见解。此外，它可能会为治疗充血性心力衰竭和其他情况（例如衰老）提供一种全新的治疗方法，这种方法基于 ACTH 受体拮抗剂，显示出交感神经活性的增强。