Molecular regulation of sympathetic neuron activity in cardiovascular disease

心血管疾病中交感神经元活动的分子调节

• 批准号: 10821971
• 负责人: Elizabeth Akin
• 金额: $ 21.12万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-03-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10821971
• 关键词: Adrenergic beta-Antagonists; Amino Acids; Autonomic nervous system; Axon; Axonal Transport; Cardiac; Cardiac Output; Cardiovascular Diseases; Cardiovascular system; Centers of Research Excellence; Clinical; Development; Disease; Disease Progression; Heart Contractilities; Heart Rate; Heart failure; Human; Image; Imaging Techniques; Inflammation; Inflammatory; Ion Channel; Kinesin; Measures; Microfluidics; Molecular; Molecular Motors; Motor; Neurons; Neurotransmitters; Nevada; Norepinephrine; Optics; Outcome; Pathway interactions; Patients; Physiologic pulse; Plasma; Proteins; Regulation; Resolution; Signal Transduction; Therapeutic Intervention; Up-Regulation; Vesicle; Visualization; beta-adrenergic receptor; cytokine; neonatal mice; neuropeptide Y; novel imaging technique; novel therapeutic intervention; rab GTP-Binding Proteins; response; single molecule; trafficking

The autonomic nervous system is a key regulator of the cardiovascular system including cardiac output. During disease states such as cardiac failure, autonomic input becomes unbalanced such that the sympathetic branch is overactivated and the parasympathetic branch shows decreased activity. However, the molecular mechanisms underlying these changes in neuronal activity are largely unknown. Increased sympathetic activation is characterized by increased plasma levels of neurotransmitters and are associated with poor clinical outcomes in human patients with heart failure. This includes the primary neurotransmitter norepinephrine (NE) that acts through beta-adrenergic receptors to increase heart rate and contractility, as well a 36 amino-acid co-transmitter neuropeptide Y (NPY) that is co-released under conditions of higher stimulation. We hypothesize that inflammatory signals that are elevated during cardiovascular disease potentiate NPY trafficking and release, contributing to disease progression. Although treatments such as the use of beta-blockers can help stabilize or slow disease progression for patients with heart failure, currently disease progression cannot be reversed in most cases. Thus, understanding the molecular changes that underly the dynamic regulation of sympathetic neurons will enable the development of novel therapeutic interventions. We recently developed a novel imaging technique, optical pulse-chase axonal long-distance (OPAL) imaging, that enables the visualization of axonal trafficking of low-abundance proteins such as ion channels with single-molecule resolution. Using this and other imaging techniques, we propose to investigate the alterations to NPY trafficking in cardiac sympathetic neurons from neonatal mice cultured in compartmentalized microfluidic chambers. We will investigate the molecular motors and trafficking machinery involved in the long-distance axonal transport of NPY-containing vesicles, including Rab-GTPases and kinesin motors. Elucidation of this pathway will provide targets of opportunity for therapeutic interventions for conditions such as cardiac failure. Additionally, we propose to investigate the dynamic upregulation of cardiac sympathetic neurons in response to inflammatory agents (inflammatory cytokines or byproducts of inflammation), using alterations to NPY vesicular trafficking as measure of neuronal activation.

自主神经系统是心血管系统（包括心输出量）的关键调节剂。 在诸如心脏衰竭之类的疾病状态下，自主分量的输入变得不平衡，使得 交感神经分支过度激活，副交感神经分支显示活性下降。然而， 神经元活性中这些变化的分子机制在很大程度上未知。增加 交感神经激活的特征是神经递质的血浆水平升高，并且是 与心力衰竭的人类患者的临床结局不良有关。这包括主要 神经递质去甲肾上腺素（NE）通过β-肾上腺素能受体起作用以提高心率 和收缩性，以及36个氨基酸的共染色器神经肽Y（NPY） 较高刺激的条件。我们假设在 心血管疾病增强了NPY运输和释放，导致疾病进展。 尽管诸如使用β受体阻滞剂之类的治疗方法可以帮助稳定或减缓疾病的进展 在大多数情况下，心力衰竭的患者目前无法逆转疾病进展。因此， 了解交感神经元动态调节的分子变化将 实现新的治疗干预措施的发展。我们最近开发了一种新颖的成像 技术，光学脉冲轴突长距离（OPAL）成像，可视化 低丰度蛋白的轴突运输，例如具有单分子分辨率的离子通道。使用 这种和其他成像技术，我们建议研究心脏贩运的变化 来自隔室微流体腔中培养的新生小鼠的交感神经元。我们将 研究与长距离轴突运输有关的分子电动机和运输机制 含NPY的囊泡，包括Rab-GTPases和驱动蛋白电动机。阐明这一途径将 为心脏衰竭等疾病提供治疗干预措施的机会。 此外，我们建议研究心脏交感神经元的动态上调 对炎症剂的反应（炎症细胞因子或炎症的副产物），使用改变 作为神经元激活的量度。