A novel electroceutical tool for treatment of kidney-based diseases

摘要 慢性肾神经过度活动导致肾功能的生理和病理变化， 增加肾脏疾病的风险。高血压与交感神经活性增加有关。 临床前模型中的肾脏，在大多数这些模型中，高血压通过去肾神经来减轻。 (RDN)。建立在这些模型基础上的临床试验表明，基于导管的RDN在 降低高血压患者的动脉压。经导管RDN治疗高血压的成功经验 催生了新兴的电针领域，这一领域基于器官特异性的概念 神经调节(而不是消融)治疗心脏代谢性疾病。鉴于消融是不可逆转的，而且 非三次调节的神经调节可以结合到闭环反馈设计中，以精确调节 根据需要的神经活动。此外，神经调节可以在需要时关闭和重新启动。 总而言之，我们的实验室对肾神经在肾炎发病机制中的作用有广泛的了解。 复方丹参降压作用及其机制的实验研究 奥斯本)以及开发用于设计神经技术的计算建模工具的经验(Co-PI 约翰逊。我们的目标是将这些知识转化为一种新的植入性技术的开发 肾脏神经调节治疗神经介导的大动物肾脏病理 肾病理模型(DOCA-盐羊)。在特定的目标1中，我们将研制一种双向肾神经袖带。 界面，首先在硅胶中，然后在实验室中，以电阻断(E-Block)和感觉(E-Sense)肾神经活动 在绵羊身上。在特定目标2中，我们将通过比较急性心肌梗死患者肾脏E-阻滞剂的刺激参数来优化体内的刺激参数。 麻醉DOCA-高血压患者手术消融后对E受体阻滞剂的肾脏反应 羊。这种治疗肾脏疾病的神经调节工具的成功开发可以转化为 治疗其他与肾神经过度活动有关的慢性疾病，包括慢性肾脏疾病和 终末期肾衰。此外，这项相同的技术可能被用来调节其他器官(例如， 肝、胰腺、脾)用于治疗与过度神经有关的慢性心脏代谢性疾病 活动。

ABSTRACT Chronic overactivity of renal nerves results in physiological and pathological changes in renal function that contribute to kidney-based diseases. Hypertension is correlated with increased activity of sympathetic nerves to the kidneys in preclinical models, and in most of these models, hypertension is attenuated by renal denervation (RDN). Clinical trials building on these models have demonstrated that catheter-based RDN is effective in lowering arterial pressure in hypertensive patients. The success of catheter-based RDN to treat hypertension has catalyzed the emerging field of electroceuticals, which is based on the concept of organ-specific neuromodulation (rather than ablation) for cardiometabolic diseases. Whereas ablation is non-reversible and non-tritratable, neuromodulation can be incorporated into a closed-loop feedback design to precisely regulate the activity of nerves as desired. Moreover, neuromodulation can be turned off and restarted as needed. Combined, our laboratories have extensive knowledge on the role of renal nerves in the pathogenesis of hypertension and the mechansims mediating the anti-hypertensive effect of RDN in rodent models (Co-PI Osborn) as well as experience in developing computational modeling tools to design neurotechnologies (Co-PI Johnson. We aim to translate this knowledge to the development of a novel implantable technology for neuromodulation of the kidney for treatment of neurally-mediated renal pathology in a translational large animal model of renal pathology (DOCA-salt sheep). In Specific Aim 1, we will develop a bidirectional renal nerve cuff interface, first in silico and then in the lab, to electrically block (E-Block) and sense (E-Sense) renal nerve activity in sheep. In Specific Aim 2, we will optimize stimulus parameters of renal E-block in vivo by comparing the acute renal responses to E-Block to those observed following surgical ablation in anesthetized DOCA-hypertensive sheep. Successful development of this neuromodulatory tool for treatment of renal disease can be translated to treat other chronic diseases associated with overactivity of renal nerves including chronic kidney disease and end-stage renal failure. Moreover, this same technology can potentially be used to modulate other organs (e.g. liver, pancreas, spleen) for the treatment of chronic cardiometabolic diseases that are linked to excessive nerve activity.