Cardiac afferents and renal function in heart failure

心力衰竭中的心脏传入和肾功能

• 批准号: 10558561
• 负责人: Hanjun Wang
• 金额: $ 57.17万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-18 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558561
• 关键词: Ablation; Acute myocardial infarction; Affect; Afferent Neurons; American; Capsaicin; Cardiac; Cardiac Output; Cardiorenal syndrome; Cardiovascular Diseases; Cardiovascular system; Cells; Central venous pressure; Chest; Chronic; Clinical; Complication; Congestive Heart Failure; Conscious; Coupled; Data; Denervation; Development; Diastolic blood pressure; Epidemic; Exhibits; Fiber; Functional disorder; Genetic; Grant; Heart; Heart Injuries; Heart failure; Hypothalamic structure; Injury to Kidney; Ischemia; Kidney; Kidney Failure; Laboratories; Left; Low Cardiac Output; Measures; Mediating; Medical; Metabolic; Modeling; Morbidity - disease rate; Myocardial Infarction; Nerve; Neural Pathways; Neurons; Neurotoxins; Newly Diagnosed; Pathogenesis; Pathway interactions; Patients; Persons; Plasma; Play; Prognosis; Progressive Disease; Rat Transgene; Rattus; Reflex action; Reflex control; Renal Blood Flow; Renal function; Renin-Angiotensin-Aldosterone System; Resiniferatoxin; Rodent Model; Role; Sensory; Societies; Spinal; Spinal Ganglia; Syndrome; TRPV1 gene; Techniques; Testing; Therapeutic; Thinking; United States; Vascular resistance; Vasoconstrictor Agents; Vasopressins; Venous; Ventricular; Vertebral column; Work; analog; conventional therapy; cytokine; designer receptors exclusively activated by designer drugs; genetic approach; hemodynamics; hypoperfusion; improved; innovation; kidney dysfunction; kidney vascular structure; magnocellular; mortality; neural; novel; novel therapeutics; paraventricular nucleus; prevent; receptor; renal ischemia; systemic inflammatory response; therapy development; vasoconstriction; Ablation; Acute myocardial infarction; Affect; Afferent Neurons; American; Capsaicin; Cardiac; Cardiac Output; Cardiorenal syndrome; Cardiovascular Diseases; Cardiovascular system; Cells; Central venous pressure; Chest; Chronic; Clinical; Complication; Congestive Heart Failure; Conscious; Coupled; Data; Denervation; Development; Diastolic blood pressure; Epidemic; Exhibits; Fiber; Functional disorder; Genetic; Grant; Heart; Heart Injuries; Heart failure; Hypothalamic structure; Injury to Kidney; Ischemia; Kidney; Kidney Failure; Laboratories; Left; Low Cardiac Output; Measures; Mediating; Medical; Metabolic; Modeling; Morbidity - disease rate; Myocardial Infarction; Nerve; Neural Pathways; Neurons; Neurotoxins; Newly Diagnosed; Pathogenesis; Pathway interactions; Patients; Persons; Plasma; Play; Prognosis; Progressive Disease; Rat Transgene; Rattus; Reflex action; Reflex control; Renal Blood Flow; Renal function; Renin-Angiotensin-Aldosterone System; Resiniferatoxin; Rodent Model; Role; Sensory; Societies; Spinal; Spinal Ganglia; Syndrome; TRPV1 gene; Techniques; Testing; Therapeutic; Thinking; United States; Vascular resistance; Vasoconstrictor Agents; Vasopressins; Venous; Ventricular; Vertebral column; Work; analog; conventional therapy; cytokine; designer receptors exclusively activated by designer drugs; genetic approach; hemodynamics; hypoperfusion; improved; innovation; kidney dysfunction; kidney vascular structure; magnocellular; mortality; neural; novel; novel therapeutics; paraventricular nucleus; prevent; receptor; renal ischemia; systemic inflammatory response; therapy development; vasoconstriction

Project Summary Chronic heart failure (CHF) is a growing epidemic in western societies. In the United States alone, approximately 6 million people live with CHF. In late stage CHF, renal failure is a complication that results in worsening heart failure. Patients exhibiting the cardio-renal syndrome have an extremely poor prognosis. Medical therapy for this syndrome has been ineffective. A new way of thinking about the mechanisms responsible for worsening renal function in CHF is necessary. During the previous cycle of this grant we elucidated an important neural pathway that not only mediates cardiac remodeling but also drives a massive increase in cardiac, renal and global sympathetic nerve activity in CHF. Ablation of this pathway markedly improves survival in the post MI-CHF rodent model. The Cardiac Sympathetic Afferent Reflex (CSAR) is mediated, in large part, by epicardial, TRPV1 receptor-expressing sensory endings whose cell bodies reside in the thoracic dorsal root ganglia. Here, we propose to build on our previous work by demonstrating an important role for cardiac spinal afferents in mediating renal dysfunction in severe CHF. Based on our preliminary data and using a novel TRPV1 Cre rat coupled with chemogenetic excitation and inhibition we will demonstrate the important role that these afferents play in the pathogenesis of the cardio-renal syndrome. We will furthermore utilize the ultrapotent neurotoxin resiniferatoxin (RTX; TRPV1 specific) to therapeutically salvage renal function in CHF. These studies are highly relevant to the clinical situation and will pave the way for a novel and innovative alternative to conventional therapy.

项目摘要 慢性心力衰竭（CHF）是西方社会日益增长的流行病。仅在美国， 大约有600万人与瑞士法郎一起生活。在晚期CHF中，肾衰竭是一种并发症，导致 心力衰竭恶化。表现出心脏 - 肾脏综合征的患者的预后极差。 该综合征的医疗疗法无效。思考机制的新方法 负责使CHF中的肾功能恶化。在这笔赠款的上一个周期中，我们 阐明了一条重要的神经途径，不仅介导心脏重塑，而且驱动大量 CHF中心脏，肾脏和全球交感神经活动的增加。这条路的消融明显 改善MI-CHF后啮齿动物模型的生存。心脏交感神经传入反射（CSAR）是 在很大程度上是由心外膜的，表达TRPV1受体的感官末端的介导的，其细胞体内 胸部背根神经节。在这里，我们建议通过证明重要的 心脏脊柱传入中介导严重CHF肾功能障碍的作用。根据我们的初步数据 并使用一种新型的TRPV1 CRE大鼠加上化学兴奋和抑制作用，我们将证明 这些传入中这些传入在心脏 - 肾脏综合征的发病机理中起的重要作用。我们将进一步 利用超能力神经毒素树脂毒素（RTX; TRPV1特异）来治疗肾功能 在瑞士法郎。这些研究与临床状况高度相关，并将为小说和 常规疗法的创新替代方案。