Serotonergic control of the sympathoadrenal stress response

交感肾上腺应激反应的血清素控制

基本信息

批准号：
10654226
负责人：
KEVIN P CURRIE
金额：
$ 48.3万
依托单位：
ROWAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654226
关键词：
Action Potentials Acute Adrenal Glands Antidepressive Agents Anxiety Autonomic Dysfunction Biomedical Research Blood Calcium Catecholamines Cells Chromaffin Cells Chronic Clinical Data Disease Electrophysiology (science)Environment Epinephrine Event Excision Exocytosis Failure Functional disorder Funding G-Protein-Coupled Receptors Gene Expression Genetic Genetic Variation Glutaminase Heart failure Human Hyperalgesia Hypertension Hypoglycemia Image In Vitro Investigation Kinetics Knock-out Knockout Mice Link Measures Mediating Medical Students Mental Depression Modeling Mus Nature Nervous System Neuromodulator Neurons Neuropeptides Neurosecretory Systems Neurotransmitters Norepinephrine Obsessive-Compulsive Disorder Pathway interactions Patients Peripheral Peripheral Nervous System Diseases Pharmaceutical Preparations Physiological Physiology Play Post-Translational Protein Processing Post-Traumatic Stress Disorders Prevalence Process Publishing Receptor Inhibition Reporting Research Rodent Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Receptor 5-HT1A Signal Transduction Site Stimulus Stress Sympathetic Nervous System System Testing Tissues Tyrosine 3-Monooxygenase Up-Regulation Vesicle Work arm autism spectrum disorder biological adaptation to stress carbon fiber clinically relevant comorbidity fighting in vivo insight monoamine mouse model neurotransmitter release novel patch clamp pharmacologic physiologic stressor pituitary adenylate cyclase activating polypeptide response restraint serotonergic regulation serotonin transporter stressor therapeutic target tool undergraduate research experience undergraduate student uptake

项目摘要

The serotonin transporter (SERT) is a key physiological regulator of serotonin (5-HT) signaling and availability, and thus the diverse, clinically important roles of this neuromodulator. Genetic variations in SERT are associated with depression, anxiety, obsessive-compulsive disorder, and autism. Moreover, SERT is a clinically relevant target for antidepressant medications, including selective serotonin reuptake inhibitors (SSRI’s). In contrast to its well-known roles in CNS serotonergic neurons, the robust expression of SERT in adrenal chromaffin cells remains understudied and enigmatic. Adrenal chromaffin cells comprise the neuroendocrine arm of the sympathetic nervous system, synthesizing, storing, and secreting catecholamines (epinephrine, norepinephrine) and neuropeptides which coordinate the response to physiological stressors. Aberrant control of this sympathoadrenal stress response contributes to autonomic dysfunction and related comorbidities evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. However, the mechanisms by which SERT / 5-HT signaling controls these stress responses remain unclear. We postulate that adrenal chromaffin cells are a key peripheral hub for serotonergic regulation of the sympathetic stress response. Our published and preliminary data suggest that SERT / 5-HT signaling acts through several distinct mechanisms to exert both acute and chronic control over adrenal catecholamine secretion. We show that adrenal chromaffin cells accumulate small amounts of 5-HT due to SERT-mediated uptake and that an interplay between SERT and 5-HT1A receptors on chromaffin cells controls catecholamine secretion. Our data also point to an additional level of control in which 5-HT acts as an intracellular messenger following SERT-mediated uptake to control catecholamine exocytosis. To dissect the role of SERT, we developed the first mouse model with conditional excision of SERT in the sympathetic nervous system (SERTΔTH mice). We propose three specific aims that integrate in vivo physiology with detailed in vitro mechanistic investigations that leverage this novel mouse and the experimental advantages of adrenal chromaffin cells as a neurosecretory model: Aim-1 tests the hypothesis that the sympathoadrenal stress response is regulated by expression of SERT in adrenal chromaffin cells. Aim-2 focuses on in vitro mechanistic studies and tests the hypothesis that signaling via SERT / 5-HT1A receptors is fine-tuned to control stress-evoked catecholamine secretion. Aim-3 tests the hypothesis that 5-HT acts as an intracellular messenger following SERT-mediated uptake to control the kinetics and quantal size of vesicular neurotransmitter release. The project will provide new mechanistic understanding of the sympathoadrenal system and autonomic dysfunction associated with altered serotonergic signaling. It will also enhance the research environment and provide meaningful research experiences for undergraduate and medical students.

血清素转运蛋白 (SERT) 是血清素 (5-HT) 信号传导和可用性的关键生理调节剂，因此，这种神经调节剂的遗传变异在 SERT 中具有多种重要的临床作用。此外，SERT 与抑郁、焦虑、强迫症和自闭症有关。抗抑郁药物的临床相关目标，包括选择性血清素再摄取抑制剂（SSRI 的）与其在中枢神经系统血清素能神经元中的众所周知的作用相反，SERT 在中枢神经系统中的强烈表达。肾上腺嗜铬细胞仍处于研究之中且神秘。交感神经系统的神经内分泌臂，合成、储存和分泌儿茶酚胺（肾上腺素、去甲肾上腺素）和协调对生理应激源的反应的神经肽。这种交感肾上腺应激反应的异常控制会导致自主神经功能障碍和相关疾病患有抑郁症、焦虑症和其他与血清素信号相关的疾病的患者存在明显的合并症。然而，SERT/5-HT 信号传导控制这些应激反应的机制仍不清楚。我们假设肾上腺嗜铬细胞是血清素能调节的关键外周枢纽。我们发表的初步数据表明 SERT / 5-HT 信号传导起作用。通过几种不同的机制对肾上腺儿茶酚胺进行急性和慢性控制我们发现肾上腺嗜铬细胞由于 SERT 介导而积累少量 5-HT。摄取以及嗜铬细胞上的 SERT 和 5-HT1A 受体之间的相互作用控制儿茶酚胺我们的数据还指出了 5-HT 作为细胞内信使的额外控制水平。为了剖析 SERT 的作用，我们通过 SERT 介导的摄取来控制儿茶酚胺胞吐作用。开发了第一个交感神经系统条件性切除 SERT 的小鼠模型（SERTΔTH 小鼠）。我们提出了三个具体目标，将体内生理学与详细的体外生理学相结合。利用这种新型小鼠和肾上腺的实验优势进行机制研究嗜铬细胞作为神经分泌模型：Aim-1 检验了交感肾上腺应激的假设 Aim-2 的反应受肾上腺嗜铬细胞中 SERT 表达的调节。机制研究并测试通过 SERT / 5-HT1A 受体的信号传导经过微调以控制的假设 Aim-3 测试了 5-HT 作为细胞内物质的假设。 SERT 介导的摄取后的信使，控制囊泡的动力学和定量大小该项目将为交感肾上腺提供新的机制理解。与血清素信号改变相关的系统和自主神经功能障碍也会增强。研究环境并为本科生和医学生提供有意义的研究经验。