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、预测和控制中央脑干神经元，这些神经元将内感输入整合到 产生并测定迷走神经在调节心脏方面的活动。迷走神经流出的程度是 与心脏健康密切相关。迷走神经流出不足导致多种形式的心脏 这种疾病似乎是可以预防的，而且有可能通过心脏保护性迷走神经流出的增加而逆转。 我们的目标是研究迷走神经背侧运动核(DMV)内的中枢神经元，这是一个重要的 心脏保护性迷走神经流出到心脏的来源，因为这些与一些最具破坏性的 心脏疾病。我们将确定DMV神经元的心肌保护分子机制，以便 利用这些信息来干预和影响这些分子机制，从而允许控制迷走神经 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 在DMV神经元中的microRNAs和mRNAs(例如，Gorky等人)。2021年)。我们已经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年；高尔基，德迪科 等人的研究。回顾中)，并试图在这里效仿这一方法。我们有初步的机动车管理局数据整合了互感 心肌缺血和远程缺血预适应(RIPC)的输入表明这种方法将是 适用于雄性和雌性大鼠迷走神经心脏保护。我们假设迷走神经流出 RIPC中的心脏保护来自背侧运动核内分子活性的改变 迷走神经(DMV)，由DMV神经元中的差异microRNA调控介导。目标1将寻求 冠状动脉左前降支结扎后DMV神经元分子状态的再正常化 通过调节DMV内的microRNA调节网络。目标2将确定的动态轨迹 RIPC诱导的microRNA和DMV中的基因调控网络预测RIPC诱导的microRNA控制点 在DMV中，这可能会将分子心脏保护作用延长到目前所描述的24小时之外 RIPC后的功效窗口。目标3将测试microRNAs对RIPC的反应进行调节的假设，以及 它们的靶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 神经元。我们已经为这个项目组建了一个跨学科的团队。瓦迪帕利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和 MicroRNA网络调节器。施瓦伯博士在集成电路方面有丰富的经验 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博士是个专家 关于脑干自主神经核团中的神经元过程，并带来了关于单个神经元的技术专长 隔离和分析。这些研究将采用最先进的系统生物学和分子神经遗传学 控制系统方法，使我们能够测试新的中枢神经心脏保护假说，揭示 治疗心脏病的脑干神经元药物靶点。