Potential therapies to improve ventricular vagal function in type 2 diabetes

改善 2 型糖尿病心室迷走功能的潜在疗法

基本信息

批准号：
10222766
负责人：
Yu-Long Li
金额：
$ 38.13万
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：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222766
关键词：
Acetylcholine Address Adult Affect Animals Autonomic Dysfunction Binding Calcium Channel Cardiac Cells Chromosome Mapping Clinical Conscious Data Diabetes Mellitus Efferent Neurons Elements Encapsulated Functional disorder Ganglia Gene Silencing Genes Genetic Genetic Transcription Heart Hydrogen Peroxide Impairment In Vitro Kinetics Link Measures Mediating Messenger RNA Microinjections Molecular Myocardial Infarction Myocardial dysfunction Myocardium Nerve Neuronal Dysfunction Neurons Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Oxidative Stress Pathway interactions Patients Pharmacologic Substance Physiological Population Proteins Rattus Role Signal Pathway Signal Transduction Testing Therapeutic Transfection Ventricular Ventricular Arrhythmia Ventricular Dysfunction Ventricular Function Withdrawal attenuation base catalase curative treatments density design diabetic diabetic patient heart function improved in vivo insight mortality nanoparticle non-diabetic novel sudden cardiac death targeted treatment transcription factor voltage

项目摘要

Project Summary Diabetes-reduced cardiac vagal activity is involved in sudden cardiac death and is responsible for high mortality in diabetic patients. Increasing cardiac vagal tone significantly limits cardiac dysfunction and reduces mortality. However, the potential mechanisms involved in reduced cardiac vagal activity in type 2 diabetes mellitus (T2DM) are poorly understood. Cardiac vagal ganglionic neurons (a final common pathway for vagal control of cardiac function) regulate acetylcholine release to influence cardiac function. Ca++ influx through voltage-gated Ca++ channels is a key trigger for acetylcholine release from these neuronal terminals. Our recent study has shown that expression and current density of N-type Ca++ channels in cardiac vagal ganglionic neurons are decreased in T2DM rats. Rat cardiac vagal ganglia are divided into the sinoatrial ganglion and the atrioventricular ganglion (AVG). The ventricular myocardium only receives the projection of nerve terminals from AVG neurons. Based on our preliminary data, we hypothesize that T2DM-mediated hydrogen peroxide (H2O2) overproduction in AVG neurons inhibits N-type Ca++ channel function via repressor element 1-silencing transcription factor (REST) signaling and/or by direct action, which further contributes to attenuation of ventricular vagal neuronal function in T2DM. Using multi-faceted technical approaches ranging from whole-animals to cellular-molecular levels, we will design in vivo and in vitro studies in sham and T2DM rats to assess these questions. In Specific Aim 1, we will address if T2DM induces ventricular vagal neuronal dysfunction as measured by N-type Ca++ channel expression and activation, cell excitability, and intracellular Ca++ levels in ventricular vagal neurons, as well as ventricular acetylcholine release from vagal nerve terminals. In Specific Aim 2, we will test how H2O2 overproduction modulates function of AVG neurons in T2DM through REST signaling. In Specific Aim 3, we will determine if impairment of ventricular vagal neurons contributes to ventricular electrical and contractile dysfunction in T2DM. These studies will further our understanding of the cellular and molecular mechanisms responsible for impaired cardiac vagal activity in T2DM and will also explore potential therapeutics for improving cardiac vagal activity and reducing mortality in T2DM.

项目概要糖尿病引起的心脏迷走神经活动减少与心源性猝死有关，并且是造成这种情况的原因对于糖尿病患者的高死亡率。增加心脏迷走神经张力显着限制心脏功能障碍并降低死亡率。然而，减少涉及的潜在机制对于 2 型糖尿病 (T2DM) 中的心脏迷走神经活动知之甚少。心脏迷走神经神经节神经元（迷走神经控制心脏功能的最终共同途径）调节乙酰胆碱释放影响心脏功能。 Ca++ 通过电压门控 Ca++ 流入通道是这些神经元末梢释放乙酰胆碱的关键触发器。我们最近的研究表明心脏迷走神经中N型Ca++通道的表达和电流密度 T2DM 大鼠的神经节神经元减少。大鼠心脏迷走神经节分为窦房神经节和房室神经节（AVG）。仅心室肌接收来自AVG神经元的神经末梢的投射。根据我们的初步数据，我们假设 AVG 中 T2DM 介导的过氧化氢 (H2O2) 过量产生神经元通过阻遏元件1沉默抑制N型Ca++通道功能转录因子（REST）信号传导和/或通过直接作用，这进一步有助于 T2DM 中心室迷走神经元功能的减弱。运用多方面技术从整个动物到细胞分子水平的方法，我们将在体内设计对假大鼠和 T2DM 大鼠进行体外研究来评估这些问题。在具体目标 1 中，我们将解决 T2DM 是否诱发心室迷走神经元功能障碍（通过 N 型 Ca++ 测量）心室通道表达和激活、细胞兴奋性和细胞内 Ca++ 水平迷走神经元，以及迷走神经末梢释放的心室乙酰胆碱。在具体目标 2，我们将测试 H2O2 过量产生如何调节 AVG 神经元的功能通过 REST 信令的 T2DM。在具体目标 3 中，我们将确定心室功能是否受损迷走神经元导致 T2DM 心室电和收缩功能障碍。这些研究将进一步加深我们对细胞和分子机制的理解 T2DM 患者心脏迷走神经活动受损，还将探索改善的潜在疗法心脏迷走神经活动并降低 T2DM 死亡率。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reduced Cell Excitability of Cardiac Postganglionic Parasympathetic Neurons Correlates With Myocardial Infarction-Induced Fatal Ventricular Arrhythmias in Type 2 Diabetes Mellitus.

DOI：
10.3389/fnins.2021.721364
发表时间：
2021
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Hu W;Zhang D;Tu H;Li YL
通讯作者：
Li YL

Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure.

DOI：
10.1093/cvr/cvaa018
发表时间：
2020-01
期刊：
Cardiovascular research
影响因子：
10.8
作者：
Dongze Zhang;H. Tu;Chaojun Wang;Liang Cao;Wenfeng Hu;Bryan T. Hackfort;R. Muelleman;M. Wadman;Yu-Long Li
通讯作者：
Dongze Zhang;H. Tu;Chaojun Wang;Liang Cao;Wenfeng Hu;Bryan T. Hackfort;R. Muelleman;M. Wadman;Yu-Long Li

Editorial: Biomarkers: precision nutrition in chronic diseases.