Molecular Neurogenetics of the Brainstem Neuronal Source of Cardioprotective Vagal Outflow

心脏保护性迷走神经流出脑干神经源的分子神经遗传学

基本信息

批准号：
10641909
负责人：
JAMES SCHWABER
金额：
$ 57.11万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641909
关键词：
Affect Anatomy Anterior Anterior Descending Coronary Artery Arteries Behavior Biological Assay Brain Stem Cardiac Cardiac health Cardiovascular system Cell Nucleus Complex Computer Analysis Data Data Set Development Dorsal Extinction Female Gene Expression Genes Genetic Transcription Heart Heart Diseases Hour Hypertension Immunohistochemistry In Situ Hybridization Intervention Studies Ischemic Preconditioning Left Ligation Mediating Mediator Messenger RNA MicroRNAs Molecular Motor Neurons Myocardial Ischemia Neuroanatomy Neurons Pathologic Pattern Peripheral Phase Phenotype Physiological Physiology Process Rattus Regulation Reperfusion Injury Research Series Source System Systems Biology Technical Expertise Testing Time Untranslated RNA Vagus nerve structure antagonist cardioprotection cohort computational network modeling data integration dorsal motor nucleus druggable target experience experimental analysis gene regulatory network genomic platform injury and repair insight interest ischemic injury laser capture microdissection male miRNA expression profiling molecular phenotype multidimensional data nano-string neurogenetics neurophysiology pharmacologic protective effect remote intervention response restoration single-cell RNA sequencing skills transcriptome sequencing transcriptomic profiling transcriptomics

项目摘要

We aim to identify, predict and control the central brainstem neurons that integrate interoceptive inputs to produce and determine the activity of the vagus nerve in regulating the heart. The level of “vagal outflow” is strongly associated with the health of the heart. Insufficient vagal outflow contributes to many forms of heart disease, which appear preventable and, potentially, reversible by increases in cardioprotective vagal outflow. We aim to study the central neurons within the dorsal motor nucleus of the vagus (DMV) that are an important source of cardioprotective vagal outflow to the heart, as these are associated with some of the most devastating diseases of the heart. We will determine the cardioprotective molecular mechanisms in DMV neurons in order to use this information to intervene and affect those molecular mechanisms in ways that allow control of the vagal outflow. We will accomplish this through an integrated experimental and computational analysis of the responses of microRNAs and mRNAs in DMV neurons (e.g., Gorky et al. 2021). We have successfully followed this approach using microRNA regulation in a parallel project on hypertension (DeCicco et al. 2015; Gorky, DeDicco et al. in review), and seek to emulate that approach here. We have preliminary DMV data integrating interoceptive inputs in cardiac ischemia and remote ischemic preconditioning (rIPC) suggesting this approach will be applicable for vagal cardioprotection in male and female rats. We hypothesize that the vagal outflow that drives cardioprotection in rIPC derives from an altered molecular activity within the dorsal motor nucleus of the vagus (DMV), mediated by differential microRNA regulation in DMV neurons. Aim 1 will seek to renormalize the molecular state of DMV neurons following left anterior descending coronary artery (LAD) ligation by modulating the microRNA regulatory networks within the DMV. Aim 2 will identify the dynamic trajectory of rIPC-induced microRNA and gene regulatory networks in DMV to predict rIPC-induced microRNA control points in DMV that can potentially extend the molecular cardioprotective effect beyond the currently described 24-hour efficacy window post rIPC. Aim 3 will test the hypothesis that microRNAs regulated in response to rIPC, and their targets putatively contributing to cardioprotection, are co-regulated in one or more specific subsets of DMV neurons. We have assembled an interdisciplinary team for this project. Dr. Vadigepalli is a systems biologist with skills in the analysis of high-dimensional datasets to derive predictions of transcriptional network modules and of microRNA network regulators. Dr. Schwaber has extensive experience with the integrative circuit neuroanatomy and neurophysiology of the central mechanisms of vagal cardiac activity. Dr. Brailoiu is an expert on neuronal processes in the brainstem autonomic nuclei and brings technical expertise on single neuron isolation and analysis. These studies will take state-of-the-art molecular neurogenetics of systems biology and control systems approaches, to enable test of our new central neuronal cardioprotection hypothesis, revealing brainstem neuronal druggable targets for treatment of heart disease.

我们的目标是识别、预测和控制中枢脑干神经元，这些神经元将内感受输入整合到产生并决定迷走神经调节心脏的活动“迷走神经流出”的水平是。与心脏健康密切相关。迷走神经流出不足会导致多种形式的心脏疾病。这种疾病似乎是可以预防的，并且可能可以通过增加心脏保护性迷走神经流出来逆转。我们的目标是研究迷走神经背运动核 (DMV) 内的中枢神经元，这是一个重要的神经元。心脏保护性迷走神经流出心脏的来源，因为这些与一些最具破坏性的我们将确定 DMV 神经元的心脏保护分子机制，以便利用这些信息以控制迷走神经的方式干预和影响这些分子机制我们将通过对响应的综合实验和计算分析来实现这一目标。 DMV 神经元中的 microRNA 和 mRNA 的变化（例如，Gorky 等人，2021）。在高血压平行项目中使用 microRNA 调节的方法（DeCicco 等人，2015；Gorky，DeDicco 等人正在审查），并试图在这里模仿这种方法，我们有初步的 DMV 数据整合内感受。心脏缺血和远程缺血预处理（rIPC）的输入表明这种方法将是适用于雄性和雌性大鼠的迷走神经心脏保护。 rIPC 中的心脏保护作用源自背运动核内分子活动的改变目标 1 将寻求通过 DMV 神经元中的差异 microRNA 调节介导的迷走神经 (DMV)。左冠状动脉前降支 (LAD) 结扎后 DMV 神经元的分子状态重新正常化通过调节 DMV 内的 microRNA 调控网络，Aim 2 将确定其动态轨迹。 rIPC 诱导的 microRNA 和 DMV 中的基因调控网络可预测 rIPC 诱导的 microRNA 控制点 DMV 中的分子心脏保护作用可能会超出目前描述的 24 小时 rIPC 后的功效窗口将检验 microRNA 响应 rIPC 进行调节的假设，以及他们的目标被认为有助于心脏保护，在 DMV 的一个或多个特定子集中共同调节我们为这个项目组建了一个跨学科团队。Vadigepalli 博士是一位系统生物学家。分析高维数据集以得出转录网络模块预测的技能 Schwaber 博士在集成电路方面拥有丰富的经验。 Brailloiu 博士是迷走神经心脏活动中心机制的神经解剖学和神经生理学专家。研究脑干自主核中的神经元过程，并带来单个神经元的技术专业知识这些研究将采用最先进的系统生物学分子神经遗传学和控制系统方法，以测试我们新的中枢神经元心脏保护假设，揭示用于治疗心脏病的脑干神经元药物靶点。