Spinal Neuraxial Modulation of Ventricular Arrhythmias - Mechanisms and Treatment

室性心律失常的脊髓神经调节 - 机制和治疗

• 批准号: 10207745
• 负责人: Kimberly Howard-Quijano
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207745
• 关键词: Achievement; Acute; Address; Affect; Aman; Anesthesiology; Animals; Apoptosis; Arrhythmia; Attenuated; California; Cardiac; Cardiovascular system; Cause of Death; Chest; Chronic; Communication; Development; Electrophysiology (science); Epidural Anesthesia; Event; Faculty; Foundations; Functional disorder; Goals; Heart; Heart Abnormalities; Heart Diseases; Human; Human Characteristics; Inflammation; Intervention; Investigation; Ischemia; Knowledge; Label; Laboratories; Los Angeles; Measures; Mentors; Methods; Modeling; Molecular; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Neural Pathways; Neurons; Neurostimulation procedures of spinal cord tissue; Nociception; Output; Pathologic; Pathway interactions; Physicians; Play; Pre-Clinical Model; Prevention; Preventive therapy; Research; Role; Science; Scientist; Signal Pathway; Spinal; Spinal Cord; Spinal Ganglia; Tachyarrhythmias; Techniques; Training Programs; United States; Universities; Ventricular; Ventricular Arrhythmia; Work; cardioprotection; career; career development; clinical translation; design; effective therapy; gamma-Aminobutyric Acid; heart rhythm; innovation; insight; interest; member; mortality; neural circuit; neural network; neurochemistry; neuroregulation; neurotransmission; novel; novel therapeutics; painful neuropathy; porcine model; prevent; relating to nervous system; response; sudden cardiac death; transcriptome; transcriptome sequencing; Achievement; Acute; Address; Affect; Aman; Anesthesiology; Animals; Apoptosis; Arrhythmia; Attenuated; California; Cardiac; Cardiovascular system; Cause of Death; Chest; Chronic; Communication; Development; Electrophysiology (science); Epidural Anesthesia; Event; Faculty; Foundations; Functional disorder; Goals; Heart; Heart Abnormalities; Heart Diseases; Human; Human Characteristics; Inflammation; Intervention; Investigation; Ischemia; Knowledge; Label; Laboratories; Los Angeles; Measures; Mentors; Methods; Modeling; Molecular; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Neural Pathways; Neurons; Neurostimulation procedures of spinal cord tissue; Nociception; Output; Pathologic; Pathway interactions; Physicians; Play; Pre-Clinical Model; Prevention; Preventive therapy; Research; Role; Science; Scientist; Signal Pathway; Spinal; Spinal Cord; Spinal Ganglia; Tachyarrhythmias; Techniques; Training Programs; United States; Universities; Ventricular; Ventricular Arrhythmia; Work; cardioprotection; career; career development; clinical translation; design; effective therapy; gamma-Aminobutyric Acid; heart rhythm; innovation; insight; interest; member; mortality; neural circuit; neural network; neurochemistry; neuroregulation; neurotransmission; novel; novel therapeutics; painful neuropathy; porcine model; prevent; relating to nervous system; response; sudden cardiac death; transcriptome; transcriptome sequencing

ABSTRACT This proposal describes the five-year mentored training program designed to facilitate the career development of Kimberly Howard-Quijano MD MS into an independent physician-scientist capable of high-level scientific investigation. Dr. Howard has a long-standing interest in cardiovascular science and a demonstrated commitment to research. She is currently a junior faculty member in the division of Cardiothoracic Anesthesiology at the University of California at Los Angeles (UCLA) and has joined the laboratory of Drs. Aman Mahajan and Yibin Wang, investigating neuraxial modulation of ventricular arrhythmias. Dr. Howard has a strong background in academic science, completed a Masters of Research at UCLA, and seeks to develop a research path beginning with mentored investigations into the mechanisms of spinal control of myocardial excitability, which will lead to an independent research career devoted to investigating neuraxial therapies in treatment of ventricular arrhythmias. Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is the leading cause of mortality in the United States. Neuraxial interventions at the spinal level have been demonstrated to provide an important avenue for novel therapies aimed at ventricular arrhythmias and SCD. However, the mechanisms through which neuraxial modulation are affecting myocardial arrhythmogenesis remain to be defined. The objective of this proposal is to determine how spinal cord processing of cardiac neural impulses controls ventricular excitability after Chronic MI and to explain how spinal cord stimulation (SCS) therapy works, thus providing a rational basis for optimizing its efficacy in preventing cardiac dysfunction. The central hypothesis of this proposal is that Chronic MI triggers pathologic remodeling of cardiospinal neural circuits which increase myocardial sympathoexcitation. SCS therapy reduces sympathetic output through inhibitory cardioneural pathways (e.g. GABA), reducing ventricular excitability and arrhythmias after Chronic MI. The proposed studies will use an innovative preclinical model of Chronic MI which mimics ischemic heart disease in the human condition, to address the current gap in knowledge regarding the cardiospinal neural interactions that control myocardial sympathoexcitation after Chronic MI. The results of the proposed studies with acute ischemia in chronic MI hearts (Aim 1), will establish the cardiospinal neural network through which myocardial excitability is controlled and will reveal important cellular and molecular mechanisms responsible for the abnormal excitability in the diseased heart. Understanding the spinal neural pathways, through which ischemia induces myocardial sympathoexcitation, will provide the foundation to define the neurochemical signaling pathways and molecular mechanisms through which SCS reduces cardiac arrhythmias (Aim 2). Achievement of these investigations will yield important insights into the mechanisms of neuromodulation therapies, allowing expansion of their use and further development of novel treatments to prevent cardiac dysfunction and SCD.

抽象的 该建议描述了旨在促进职业发展的五年指导培训计划 Kimberly Howard-Quijano MD MS，成为一个具有高级科学的独立医师科学家 调查。霍华德博士对心血管科学有长期的兴趣，并展示了 对研究的承诺。她目前是心胸科的初级教师 加利福尼亚大学洛杉矶分校（UCLA）麻醉学，并加入了博士实验室。阿曼 Mahajan和Yibin Wang，研究心室心律不齐的神经调节。霍华德博士有很强 学术科学背景，在加州大学洛杉矶分校完成了研究硕士学位，并寻求开发研究 路径是从对心肌兴奋性脊柱控制机制的指导研究开始的， 这将导致独立的研究职业，致力于研究神经疗法 心室心律不齐。 由于心室心律不齐而导致的心脏猝死（SCD）是曼联死亡的主要原因 国家。已证明在脊柱水平上进行神经干预措施为 针对心室心律失常和SCD的新型疗法。但是，神经术的机制 调节正在影响心律失常发生，仍有待定义。该提议的目的是 确定心脏神经脉冲的脊髓加工如何控制慢性后的心室兴奋性 MI并解释脊髓刺激（SCS）疗法的工作原理，从而提供了优化的合理基础 它在预防心脏功能障碍方面的功效。该提议的中心假设是慢性MI触发器 心肌兴奋的心脏脊髓神经回路的病理重塑。 SCS 治疗通过抑制性心脏途径（例如GABA）减少交感神经输出，减少心室 慢性MI后的兴奋性和心律不齐。拟议的研究将使用创新的临床前模型 慢性MI在人类病中模仿缺血性心脏病，以解决当前知识的差距 关于控制心肌交感神经激素后慢性MI后的心脊神经相互作用。这 在慢性MI心脏中使用急性缺血的拟议研究结果（AIM 1）将建立心脏脊髓 心肌兴奋性受到控制并将揭示重要的细胞和分子的神经网络 导致患病心脏异常兴奋性的机制。了解脊柱神经 缺血引起心肌交感神经的途径将为定义提供基础 SCS的神经化学信号通路和分子机制可降低心脏 心律不齐（AIM 2）。这些调查的实现将产生对机制机制的重要见解 神经调节疗法，允许扩大其使用并进一步开发新的治疗方法 预防心脏功能障碍和SCD。