Cardiac afferents and renal function in heart failure

项目摘要 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， 约有600万人患有CHF。在晚期CHF中，肾衰竭是导致 心力衰竭恶化表现出心肾综合征的患者预后极差。 这种综合征的药物治疗一直无效。一种新的思考机制的方式 导致CHF肾功能恶化的原因是必要的。在上一个赠款周期， 阐明了一个重要的神经通路，不仅介导心脏重塑，而且还驱动大量的 CHF患者心、肾和全身交感神经活动增加。这条通路的消融 改善MI-CHF后啮齿动物模型的存活率。心脏交感传入反射（CSAR） 在很大程度上由心外膜介导，TRPV 1受体表达感觉末梢，其细胞体驻留在 胸背根神经节在这里，我们建议通过展示一个重要的 心脏脊髓传入神经在介导严重CHF肾功能不全中的作用根据我们的初步数据 并使用一种新的TRPV 1 Cre大鼠与化学遗传学的兴奋和抑制相结合，我们将证明 这些传入神经在心肾综合征的发病机制中起重要作用。我们将进一步 利用超强效神经毒素树脂毒素（RTX; TRPV 1特异性）治疗性挽救肾功能 单位：瑞士法郎。这些研究与临床情况高度相关，将为一种新的、 传统疗法的创新替代品。

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.