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: 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
• 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

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、预测和控制整合内感受性输入的中央脑干神经元， 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。迷走神经流出不足导致许多形式的心脏病 这种疾病似乎可以通过增加心脏保护性迷走神经流出来预防，并且可能是可逆的。 我们的目的是研究迷走神经背侧运动核（DMV）内的中枢神经元，这些神经元是一个重要的神经元。 心脏保护迷走神经流出心脏的来源，因为这些与一些最具破坏性的 心脏疾病。我们将确定DMV神经元中的心脏保护分子机制， 利用这些信息来干预和影响那些分子机制，从而控制迷走神经， 外流我们将通过对响应的综合实验和计算分析来实现这一点 DMV神经元中的microRNA和mRNAs（例如，Gorky等人，2021年）。我们成功地遵循了这一点 在高血压的平行项目中使用microRNA调节的方法（DeCicco等人，2015; Gorky，DeDicco 等，在回顾），并试图模仿这种方法在这里。我们有初步的车管所数据 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。我们假设迷走神经流出 驱动rIPC中的心脏保护作用来自背侧运动核内改变的分子活性 迷走神经（DMV）的，由DMV神经元中的差异microRNA调节介导。目标1将寻求 左冠状动脉前降支结扎后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。目标2将确定 rIPC诱导的microRNA和DMV中的基因调控网络，以预测rIPC诱导的microRNA控制点 在DMV中，它可以潜在地将分子心脏保护作用延长到目前描述的24小时之外， rIPC后的有效性窗口。目的3将检验microRNA响应rIPC进行调节的假设， 它们的靶点有助于心脏保护，在DMV的一个或多个特定亚群中共同调节 神经元我们为这个项目组建了一个跨学科的团队。Vadigepalli博士是一位系统生物学家， 分析高维数据集以获得转录网络模块的预测的技能， microRNA网络调节器。Schwaber博士在集成电路方面拥有丰富的经验 迷走神经心脏活动中枢机制的神经解剖学和神经生理学。Brailoiu博士是一位专家 在脑干自主神经核的神经元过程，并带来了技术专长，对单个神经元 分离和分析。这些研究将采用最先进的系统生物学分子神经遗传学， 控制系统的方法，使我们的新的中央神经元心脏保护假设的测试，揭示 用于治疗心脏病的脑干神经元可药用靶点。