A novel electroceutical tool for treatment of kidney-based diseases

一种治疗肾脏疾病的新型电疗法工具

基本信息

批准号：
10455432
负责人：
Matthew Douglas Johnson
金额：
$ 23.13万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455432
关键词：
Ablation Action Potentials Acute Albuminuria Algorithms Animal Model Antihypertensive Agents Attenuated CD8-Positive T-Lymphocytes Cardiometabolic Disease Catheters Chronic Chronic Disease Chronic Kidney Failure Clinical Research Clinical Trials Collagen Computer Models Contracts DOCA Denervation Deposition Development Devices Disease Electrodes End stage renal failure Engineering Excretory function FDA approved Feedback Fibrosis Glomerular Filtration Rate Glomerulonephritis Hypertension Inflammation Inflammatory Kidney Kidney Diseases Knowledge Laboratories Lead Link Liver Macrophage Activation Manufacturer Name Measures Mediating Medical Modeling Morbidity - disease rate Mus Nerve Nerve Block Operative Surgical Procedures Organ Pancreas Pathogenesis Pathologic Pathology Patients Peripheral Nerve Stimulation Physiological Pre-Clinical Model Process Rattus Renal Blood Flow Renal function Renin Renin-Angiotensin-Aldosterone System Reporting Research Rodent Model Role Sheep Sodium Sodium Chloride Spleen Stimulus System Technology Testing Translating United States Vascular resistance Water base comparative efficacy cytokine design experience experimental study glomerular filtration hypertension treatment hypertensive in silico in vivo interstitial kidney vascular structure mortality neuroregulation neurotechnology novel pre-clinical preclinical study pressure prevent relating to nervous system renal artery response success therapeutic target tool

项目摘要

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.

抽象的肾神经的慢性过度活动导致肾功能的生理和病理变化，有助于肾脏疾病。高血压与交感神经活动增加相关临床前模型中的肾脏，并且在大多数这些模型中，高血压通过肾脏去神经支配而减弱（RDN）。基于这些模型的临床试验表明，基于导管的 RDN 在以下方面是有效的：降低高血压患者的动脉压。基于导管的 RDN 治疗高血压的成功促进了电子药物的新兴领域，该领域基于器官特异性的概念针对心脏代谢疾病的神经调节（而不是消融）。鉴于消融是不可逆的并且不可三重调节的神经调节可以纳入闭环反馈设计中以精确调节神经的活动如所期望的。此外，神经调节可以根据需要关闭和重新启动。总之，我们的实验室对肾神经在肾病发病机制中的作用拥有广泛的知识。高血压以及 RDN 在啮齿动物模型中介导抗高血压作用的机制 (Co-PI Osborn）以及开发计算建模工具来设计神经技术的经验（Co-PI 约翰逊.我们的目标是将这些知识转化为新型植入技术的开发肾脏神经调节治疗大型动物神经介导的肾脏病理学肾脏病理模型（DOCA-盐羊）。在具体目标1中，我们将开发双向肾神经袖带接口，首先在计算机中，然后在实验室中，用于电阻断（E-Block）和感测（E-Sense）肾神经活动在羊中。在具体目标 2 中，我们将通过比较急性肾 E 阻滞体内的刺激参数来优化肾 E 阻滞的体内刺激参数。麻醉 DOCA 高血压患者手术消融后观察到的肾脏对 E-Block 的反应羊。这种用于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与肾神经过度活跃相关的其他慢性疾病，包括慢性肾病和终末期肾功能衰竭。此外，同样的技术还可以用于调节其他器官（例如，肝脏、胰腺、脾脏）用于治疗与神经过度相关的慢性心脏代谢疾病活动。