Cardiac afferents and renal function in heart failure

心力衰竭中的心脏传入和肾功能

基本信息

批准号：
10321631
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
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-18 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321631
关键词：
Ablation Acute myocardial infarction Affect Afferent Neurons American Capsaicin Cardiac Cardiac Output Cardiovascular Diseases Cardiovascular system Cells Central venous pressure Chest Chronic Clinical Complication Congestive Congestive Heart Failure Conscious Coupled Data Denervation Development Diagnosis Diastolic blood pressure Epidemic Exhibits Functional disorder Grant Heart Heart Injuries Heart failure Hypothalamic structure Injury to Kidney Kidney Kidney Failure Laboratories Left Low Cardiac Output Measures Mediating Medical Metabolic Modeling Morbidity - disease rate Myocardial Infarction Nerve Neural Pathways Neurons Neurotoxins Pathogenesis Pathway interactions Patients Persons Plasma Play Prognosis Progressive Disease 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 Transgenic Organisms United States Vascular resistance Vasoconstrictor Agents Vasopressins Venous Venous Pressure level Ventricular Work analog base conventional therapy cytokine designer receptors exclusively activated by designer drugs hemodynamics hypoperfusion improved innovation kidney dysfunction kidney vascular structure magnocellular mortality novel novel therapeutics paraventricular nucleus prevent receptor relating to nervous system renal ischemia systemic inflammatory response therapy development vasoconstriction

项目摘要

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.

项目概要慢性心力衰竭（CHF）在西方社会是一种日益严重的流行病。仅在美国，大约 600 万人患有 CHF。在 CHF 晚期，肾衰竭是一种并发症，可导致心力衰竭恶化。表现出心肾综合征的患者预后极差。对这种综合征的药物治疗无效。机制的新思考方式慢性心力衰竭 (CHF) 肾功能恶化的原因是必要的。在本次赠款的上一个周期中，我们阐明了一条重要的神经通路，它不仅介导心脏重塑，而且还驱动大量 CHF 患者的心脏、肾脏和全身交感神经活动增加。显着消融该通路提高 MI-CHF 啮齿动物模型的存活率。心脏交感传入反射 (CSAR) 是很大程度上是由心外膜表达 TRPV1 受体的感觉末梢介导的，其细胞体位于胸背根神经节。在这里，我们建议在我们之前的工作的基础上展示一个重要的心脊髓传入神经在介导严重 CHF 肾功能障碍中的作用。根据我们的初步数据并使用新型 TRPV1 Cre 大鼠以及化学遗传学激发和抑制，我们将证明这些传入神经在心肾综合征的发病机制中发挥着重要作用。我们还将进一步利用超强神经毒素树脂毒素（RTX；TRPV1 特异性）来治疗性挽救肾功能单位为瑞士法郎。这些研究与临床情况高度相关，将为新的、更有效的研究铺平道路。传统疗法的创新替代方案。