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

• 批准号: 10522387
• 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
• 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/10522387
• 关键词: Affect; Anatomy; Anterior; Anterior Descending Coronary Artery; Arteries; Behavior; Biological Assay; Brain Stem; Cardiac; Cardiac development; Cardiac health; Cardiovascular system; Cell Nucleus; Complex; Computer Analysis; Data; Data Set; Dorsal; Extinction (Psychology); Female; Gene Expression; Genes; Genetic Transcription; Heart; Heart Diseases; Hour; Hypertension; Immunohistochemistry; In Situ Hybridization; Intervention Studies; Ischemic Preconditioning; Left; Ligation; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Molecular; Myocardial Ischemia; Neuroanatomy; Neurons; Pathologic; Pattern; Peripheral; Pharmacology; 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; base; cardioprotection; cohort; computational network modeling; dorsal motor nucleus; druggable target; experience; experimental analysis; gene regulatory network; genomic platform; high dimensionality; injury and repair; insight; interest; ischemic injury; laser capture microdissection; male; miRNA expression profiling; molecular phenotype; nano-string; neurogenetics; neurophysiology; protective effect; remote intervention; response; restoration; single-cell RNA sequencing; skills; transcriptome sequencing; transcriptomics

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.

我们旨在识别，预测和控制中央脑干神经元，将互感输入整合到 在调节心脏时产生并确定迷走神经。 与心脏的健康密切相关。 疾病似乎可以预防，并且可能通过增加心脏保护性迷走神经流出而可逆。 我们旨在研究迷走神经（DMV）背运动核内的中央神经元，这是一个重要的 心脏保护迷走神经流向心脏的来源，因为某些最具破坏性的 心脏疾病。 使用此信息以控制迷走神经的方式进行干预并影响这些分子机制 流出。 DMV神经元中的microRNA和mRNA（例如，Gorky等人2021）。 在高血压的平行项目中使用microRNA调节的方法（Decicco等，2015； Gorky，Dedicco 等。 心脏缺血和远程缺血预处理（RIPC）的输入表明这种方法将为 适用于男性和雌性大鼠的迷走神经保护 在RIPC中驱动心脏保护源于背运动核内的分子活性改变 迷走神经（DMV），由DMV神经元中的MicroRNA调节介导。 在左前冠状动脉（LAD）连接后重新归一致DMV神经元的分子状态 通过调节DMV中的microRNA调节网络。 DMV中的RIPC-iicrorna和基因调节网络，以预测RIPC-I国际控制点 在DMV中，可以将分子心脏保护作用扩展到当前描述的24小时之外 功效窗口后撕裂。 他们的目标是促成心脏保护的 神经元。 分析高维数据集的技能，以得出转录模块转录和转录的转录预测 MicroRNA网络监管机构。 迷走神经活动中心机制的神经解剖学和神经生理学。 关于脑干自主核中的神经元过程，并为单个神经元带来了技术专长 分析和分析将采用系统生物学的最新分子神经遗传学 控制系统方法，以实现我们的神经元心脏保护假设的测试，揭示 脑干神经元可药物治疗心脏病的靶标。