Optogenetic modulation of cardiac vagal function improves prognosis in diabetes

心脏迷走神经功能的光遗传学调节可改善糖尿病的预后

基本信息

批准号：
10592195
负责人：
Dongze Zhang
金额：
$ 23.03万
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：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2023-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592195
关键词：
Acetylcholine Acute myocardial infarction Adrenergic Fibers Animals Anti-Arrhythmia Agents Arrhythmia Cardiac Cell physiology Cells Cervical Choline O-Acetyltransferase Clinical Conscious Data Dependovirus Development Diabetes Mellitus Diameter Disease Electric Stimulation Future Ganglia Genes Genetic Grant Heart Heart Atrium Impairment Implant Infection Inferior vena cava structure Intervention Investigation Left Left atrial structure Light Link Location Lung Myocardial Infarction Nerve Neurons Non-Insulin-Dependent Diabetes Mellitus Opsin Organ Specificity Patients Persons Population Prognosis Quality of life Rattus Regulation Reporting Right atrial structure Secure Serious Adverse Event Specificity Speed Superior vena cava structure Techniques Testing Therapeutic Time Transfection United States National Institutes of Health Veins Vena caval structure Ventricular Ventricular Arrhythmia Ventricular Function Withdrawal bench to bedside blood glucose regulation cell type cholinergic cholinergic neuron design diabetic diabetic patient external ear auricle glycemic control heart function improved improved outcome in vivo light emission miniaturize mortality neuronal circuitry neuronal excitability non-diabetic novel novel therapeutic intervention optogenetics pharmacologic promoter restoration side effect sudden cardiac death timeline wireless

项目摘要

Project Summary Vagal nerve stimulation (VNS) has emerged as a promising therapy for cardiac arrhythmia by electrical stimulation of vagal nerve at the cervical level. Direct VNS achieves its antiarrhythmic effects through increasing efferent parasympathetic input to the heart. However, patients receiving VNS have reported severe side effects, which are due to off-target stimulation of non-cardiac vagal branches. Cholinergic activation using pharmacological approaches also resulted in serious adverse events due to lack of organ specificity. Increasing vagal efferent input to the heart by targeting cardiac vagal postganglionic (CVP) neurons alone would be ideal to minimize the off-target effects and to achieve precision of parasympathetic activation for anti-arrhythmia. Here, we will introduce a miniaturized bio-optoelectronic implant that avoids limitations of VNS and pharmacological approaches by using optogenetics to treat fatal ventricular arrhythmias in type 2 diabetes mellitus (T2DM). Comparing with electrical and pharmacological approaches, optogenetics provides higher speed and accuracy in regulation of living cell function with less complications. However, a strategy of optogenetic therapy on ventricular arrhythmias in T2DM has not yet been established. Withdrawal of cardiac vagal activity is associated with ventricular arrhythmias-related sudden cardiac death and with high mortality in T2DM patients. Patients with T2DM are two to four times more likely to die from myocardial infarction (MI), compared with non-diabetic patients. Our recent study confirmed that reduction of cell excitability in CVP neurons exacerbates MI-evoked ventricular arrhythmias and mortality in T2DM animals. Considering the advantages of optogenetics including rapid, specific control of neuronal activities by light-sensitive opsins, adeno-associated virus-channelrhodopsin- 2 (AAV-ChAT-ChR2-mcherry) will be transfected into CVP neurons in T2DM animals. Specificity of neuronal expression of ChR2 (an excitatory light-sensitive opsin) in CVP neurons will be achieved by linking the choline acetyltransferase (ChAT, a specific marker of cholinergic neurons) promoter to the ChR2 gene. Continual optogenetic stimulation in CVP neurons will be achieved by illuminating a light-emitting-diodes (LED) probe that is controlled and powered wirelessly in freely moving animals. We hypothesize that optogenetic therapy could restore cell excitability of CVP neurons and acetylcholine (ACh) release from cardiac vagal nerve terminals, further improve vagal control of ventricular function and reduce acute MI-evoked ventricular arrhythmias and high mortality in T2DM. To test this hypothesis, we will determine if optogenetic restoration in CVP neuronal excitability restores ACh release from cardiac vagal nerve terminals, improves vagal control of ventricular function, and reduces MI-evoked fatal ventricular arrhythmias and high mortality in T2DM animals. This proposal will establish the first evidence of the optogenetic therapy on MI-evoked ventricular arrhythmias and mortality in T2DM, and may provide a new therapeutic strategy for improving outcomes and quality of life in T2DM patients.

项目概要迷走神经刺激（VNS）已成为一种有前途的电疗法治疗心律失常刺激颈部迷走神经。直接 VNS 通过增加抗心律失常作用来实现副交感神经传出至心脏。然而，接受 VNS 的患者报告了严重的副作用，这是由于非心脏迷走神经分支的脱靶刺激所致。胆碱能激活使用由于缺乏器官特异性，药理学方法也会导致严重的不良事件。增加通过单独针对心脏迷走神经节后（CVP）神经元将迷走神经传出输入输入到心脏将是理想的以最大限度地减少脱靶效应并实现副交感神经激活的精确性以抗心律失常。这里，我们将推出一种小型化的生物光电植入物，它可以避免 VNS 和药理学的限制使用光遗传学方法治疗 2 型糖尿病 (T2DM) 中的致命性室性心律失常。与电学和药理学方法相比，光遗传学提供了更高的速度和准确性调节活细胞功能，并发症较少。然而，光遗传学治疗策略 T2DM 中的室性心律失常尚未确定。心脏迷走神经活动的减弱与室性心律失常相关的心源性猝死以及 T2DM 患者的高死亡率。患者患有与非糖尿病患者相比，T2DM 患者死于心肌梗塞 (MI) 的可能性高出两到四倍患者。我们最近的研究证实，CVP 神经元细胞兴奋性的降低会加剧 MI 诱发的症状 T2DM 动物的室性心律失常和死亡率。考虑到光遗传学的优点包括通过光敏视蛋白、腺相关病毒通道视紫红质快速、特异性地控制神经元活动 2 (AAV-ChAT-ChR2-mcherry) 将被转染到 T2DM 动物的 CVP 神经元中。神经元的特异性 ChR2（一种兴奋性光敏视蛋白）在 CVP 神经元中的表达将通过连接胆碱来实现 ChR2 基因的乙酰转移酶（ChAT，胆碱能神经元的特定标记）启动子。连续 CVP 神经元的光遗传学刺激将通过照亮发光二极管 (LED) 探针来实现，对自由活动的动物进行无线控制和供电。我们假设光遗传学疗法可以恢复 CVP 神经元的细胞兴奋性和心脏迷走神经释放乙酰胆碱 (ACh) 终端，进一步改善迷走神经对心室功能的控制，减少急性心肌梗死诱发的心室 T2DM 的心律失常和高死亡率。为了检验这个假设，我们将确定光遗传学恢复是否 CVP 神经元兴奋性恢复心脏迷走神经末梢的乙酰胆碱释放，改善迷走神经控制心室功能，并减少 MI 诱发的致命性室性心律失常和 T2DM 动物的高死亡率。该提案将为光遗传学治疗 MI 诱发的室性心律失常建立第一个证据和 T2DM 的死亡率，并可能为改善 T2DM 的结果和生活质量提供新的治疗策略 T2DM 患者。