Conference on Autonomic Regulation of Cardiovascular Function in Health and Disea

在过去的100年里，我们已经对调节动脉压力和外周阻力的神经机制有了全面的了解。在过去的20年里，我们已经阐明了许多控制交感神经活动的细胞和分子机制。由于缺乏对原发性高血压发病机制的了解，这方面的工作一直在进行。毫无疑问，增强的交感神经活动有助于各种疾病状态的发病机制，包括高血压、心力衰竭、糖尿病和惊恐障碍。我们现在有能力了解在疾病状态下改变交感神经活动的离散分子机制。这些机制改变了特定的离子通道功能和膜特性，从而引起交感神经兴奋。目前高血压和心力衰竭的治疗在很大程度上是针对交感神经系统和肾素-血管紧张素II系统（RAS）。这些疗法的有效性是由于这些系统的强烈激活。不幸的是，这些治疗模式多年来一直没有改变。尽管近年来新的药物治疗方法略有改善，但很大一部分患者对这些治疗方法难治。这一事实促使科学界研究药物干预的新目标，并寻求高血压和心力衰竭的器械治疗。后者的例子是肾交感神经去支配和颈动脉窦压力感受器刺激治疗耐药高血压患者。此外，利用新的载体将蛋白质和基因传递到自主调节的离散区域，以及生理参数的慢性记录技术的出现，比历史上任何时候都更能为发现新的治疗靶点提供工具。后者的一个例子是Lindley和他的同事(Circulation Research 94:402-409, 2004; Am。[j] .中国生物医学工程学报，2009(6):518 - 518。2009)在心力衰竭小鼠的皮质下器官中转染超氧化物歧化酶，不仅可以减少交感神经活动，而且实际上可以改善心功能。新的纳米颗粒递送技术可用于中枢神经系统的靶向治疗，以治疗以交感神经兴奋为特征的疾病。这次美国生理学会（APS）会议将集中讨论这些机制。会议将包括自分泌、旁分泌和内分泌介质对反射的作用，以及已知调节交感神经功能的中枢神经系统区域（如下丘脑和髓质）。专题讨论会和海报报告将集中于反应性氧化应激、一氧化氮、血管紧张素II、血管紧张素（1-7）、谷氨酸、GABA和许多这些介质受体的转录和翻译调节。本次会议将讨论的研究领域对于原发性自主神经疾病的治疗和管理以及从心血管和/或代谢疾病演变而来的疾病的转化方法至关重要。人类、动物、细胞和分子生理学的融合将促进对这一生物医学领域其他综合方法的讨论。考虑到上述情况，拟议会议的具体目标是：汇集自主心血管生理学和病理生理学领域的领导者，就各种疾病状态下与交感神经兴奋相关的当前研究和治疗进行激烈的讨论。2. 为初级研究人员、研究生和博士后提供一个场所，以口头和海报的形式展示他们的研究。3. 促进新思想的产生，目标是将基础科学转化为临床治疗。4. 在心血管功能自主调节领域建立新的研究者关系。5. 提供一个国际论坛，使代表性不足的少数民族能够参与。公共卫生相关性：本次会议的目的是提供一个科学论坛，交流思想，并介绍有关健康和疾病中交感神经活动调节的最新数据。交感神经激活虽然被认为是动脉压力、血流和血管阻力的生理相关和重要调节因子，但如果过度活跃，则被认为有助于病理。在那些情况下尤其如此

DESCRIPTION (provided by applicant): Specific Aims Over the past 100 years we have acquired a comprehensive understanding of the neural mechanisms that regulate arterial pressure and peripheral resistance. In the past 20 years we have elucidated many cellular and molecular mechanisms that control sympathetic nerve activity. Much of this work has been driven by a lack of understanding of the mechanisms responsible for the development of essential hypertension. There is little doubt that augmented sympathetic nerve activity contributes to the pathogenesis of a variety of disease states including hypertension, heart failure, diabetes and panic disorders. We now have the capability to understand discrete molecular mechanisms responsible for altering sympathetic nerve activity in disease states. These mechanisms alter specific ion channel function and membrane properties in order to evoke sympatho-excitation. Current therapy for hypertension and heart failure, in large part, target the sympathetic nervous system and the renin- angiotensin II system (RAS). The effectiveness of these therapies is due to the intense activation of these systems. Unfortunately, these treatment paradigms have not changed for many years. In spite of the fact that new pharmacological therapies have slightly improved outcomes in recent years a large segment of patients are refractory to these treatments. This fact has prompted the scientific community to investigate new targets for pharmacological intervention and to look to device therapy for hypertension and heart failure. Examples of the latter are renal sympathetic nerve denervation and carotid sinus baroreceptor stimulation for treatment of patients with drug-resistant hypertension. Furthermore, the utilization of novel vectors for the delivery of proteins and genes to discrete areas of autonomic regulation and the advent of chronic recording techniques of physiological parameters has, more than any other time in history, provided the tools to discover new targets for therapy. An example of the latter is the demonstration by Lindley and coworkers (Circulation Research 94:402-409, 2004; Am. J. Physiol. 296:R1-R8. 2009) that transfection of the subfornical organ with superoxide dismutase in mice with heart failure, not only reduces sympathetic nerve activity but actually improves cardiac function. New nanoparticle delivery techniques can be utilized for targeted therapy to the central nervous system for the treatment of diseases characterized by sympathoexcitation. This American Physiological Society (APS) conference will focus on many of these mechanisms. Sessions will include the role of autocrine, paracrine and endocrine mediators of reflexes and areas of the central nervous system that are known to regulate sympathetic function (e.g. the hypothalamus and medulla). Symposia and poster presentations will focus on reactive oxidant stress, nitric oxide, angiotensin II, angiotensn (1-7), glutamate, GABA and the transcriptional and translational regulation of the receptors for many of these mediators. The areas of research to be discussed at this conference are pivotal to a translational approach in the treatment and management of primary autonomic disorders and to those evolving from cardiovascular and/or metabolic diseases. The melding of human, animal, cellular and molecular physiology will foster discussion of additional integrative approaches in this area of biomedicine. With the above in mind, the specific aims of the proposed conference are: 1. Bring together leaders in the field of autonomic cardiovascular physiology and pathophysiology for an intense discussion of the current research and therapy related to sympathoexcitation in a variety of disease states. 2. Provide a venue for junior investigators, graduate students and post-doctoral fellows to highlight their research in the form of oral and poster presentations. 3. Foster the generation of new ideas targeted to the translation of basic science into clinical therapies. 4. Establish new relationships between investigators in the area of autonomic regulation of cardiovascular function. 5. Provide an international forum in which underrepresented minorities can participate. PUBLIC HEALTH RELEVANCE: The purpose of this conference is to provide a scientific forum for the exchange of ideas and the presentation of the most recent data on the regulation of sympathetic nerve activity in health and disease. Sympathetic activation, while considered a physiologically relevant and important regulator of arterial pressure, blood flow and vascular resistance, is thought to contribute to pathology, if overactive. This is especially true in those conditions that require a high level of sympathetic tone to compensate for an abnormal cardiac output or where sympathetic nervous activity sustains arterial pressure in a range that is clearly detrimental to organ function. It is critical that a comprehensive understanding of the integrative mechanisms that take part in abnormal sympathetic function take place so that more rational therapy for these disorders can be developed. In this conference we will specifically focus on disorders that have been characterized as involving abnormalities in sympathetic regulation. The meeting will take an integrative approach to understanding sympathetic regulation and will incorporate genetic, molecular, cellular and whole animal approaches to the topics covered in this conference. There has never been an APS conference on this topic. The program will incorporate several topics related to sympathetic activation. These will include symposia related to central autocrine, paracrine and endocrine influences. New data on the ACE-ACE2 balance and central cellular signaling pathways will be covered. Oxidative stress is now thought to be part of normal cell signaling and in excess to contribute to activation of excitable cells and contribute to pathology. At least 1 symposium and several talks will be dedicated to sympathetic regulation in humans. These talks will include heart failure, hypertension, POTS, panic disorder and obesity/metabolic syndrome.