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.

自主神经系统是包括心输出量在内的心血管系统的关键调节器。 在心力衰竭等疾病状态下，自主神经输入变得不平衡，从而使 交感神经分支过度激活，副交感神经分支活动减弱。然而， 这些神经元活动变化背后的分子机制在很大程度上是未知的。增加了 交感神经激活的特征是血浆神经递质水平升高， 与人类心力衰竭患者不良的临床结果有关。这包括主服务器 神经递质去甲肾上腺素(NE)通过β-肾上腺素能受体促进心率 和收缩能力，以及36个氨基酸的共同递质神经肽Y(NPY)，它在 高刺激性的条件。我们假设在治疗过程中升高的炎症信号 心血管疾病促进NPY的运输和释放，促进疾病的进展。 尽管使用β-受体阻滞剂等治疗方法可以帮助稳定或减缓疾病的进展 对于心力衰竭患者，目前在大多数情况下疾病进展是无法逆转的。因此， 了解交感神经元动态调节背后的分子变化将 能够开发新的治疗干预措施。我们最近开发了一种新的成像技术 光学脉冲追逐轴突远距离成像技术，使可视化 低丰度蛋白质的轴突运输，如单分子分辨率的离子通道。vbl.使用 这项技术和其他成像技术，我们建议调查心脏NPY转运的变化 在分隔的微流体室中培养的新生小鼠的交感神经元。我们会 研究长距离轴突运输中的分子马达和运输机制 含有NPY的囊泡，包括Rab-GTP酶和运动蛋白马达。对这一途径的阐明将 为心力衰竭等疾病的治疗干预提供机会靶点。 此外，我们建议研究心脏交感神经元的动态上调。 对炎症因子(炎症细胞因子或炎症副产物)的反应，使用改变 以NPY囊泡转运作为神经元激活的量度。