The Mitochondrial Sodium/Calcium Exchanger (NCLX) in Airway Smooth Muscle Remodeling during Asthma

线粒体钠/钙交换器 (NCLX) 在哮喘期间气道平滑肌重塑中的作用

• 批准号: 10470737
• 负责人: Martin T Johnson
• 金额: $ 3.39万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470737
• 关键词: Acute; Address; Affect; Airway Disease; American; Animals; Asthma; Biogenesis; Bronchi; Buffers; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Signaling; Cell Proliferation; Cell physiology; Chronic lung disease; Clinical; Coin; Complex; Cost of Illness; Cytosol; Data; Development; Disease; Exposure to; Fibrosis; Genus Hippocampus; Gills; Goals; Healthcare Systems; Human; Immunohistochemistry; Inflammation; International; Irrigation; Kinetics; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Link; Lung; Measures; Mechanical Ventilators; Mediating; Medicine; Mentors; Metabolic; Metabolism; Metaplasia; Mitochondria; Molecular; Molecular Target; Mucous body substance; Mus; Muscle Mitochondria; Organelles; Outer Mitochondrial Membrane; Paper; Pathogenesis; Phenotype; Physicians; Proteins; Pyroglyphidae; RNA Interference; Reporting; Research; Resources; Role; Saline; Scientist; Severities; Signal Transduction; Signaling Molecule; Smooth Muscle; Smooth Muscle Myocytes; Sodium; Sodium-Calcium Exchanger; Symptoms; Techniques; Therapeutic; Training; Translating; Transmission Electron Microscopy; United States; Western Blotting; airway hyperresponsiveness; airway inflammation; airway remodeling; angiogenesis; asthma model; asthmatic; asthmatic airway; asthmatic patient; career; cell motility; chronic inflammatory disease; clinically relevant; college; cost; density; experience; extracellular; in vivo; insight; meetings; migration; mitochondrial metabolism; mouse model; new therapeutic target; novel; novel strategies; peroxisome; pulmonary function; receptor; respiratory smooth muscle; spatiotemporal; targeted treatment; treatment strategy

PROJECT SUMMARY/ABSTRACT Asthma, which has been traditionally characterized as a chronic inflammatory disease of the airways, affects 25.7 million Americans a year. The pathogenesis of this complex disease is now being recognized as not only due to inflammation but also due to structural changes in the airways known as airway remodeling (AR). Specifically, airway smooth muscle (ASM) remodeling has been demonstrated to cause a decline in pulmonary function, contribute to airway hyperresponsiveness (AHR), and worsen asthmatic symptoms. Currently, there is no targeted therapy for AR in asthma. Understanding the molecular mechanisms of AR could lead to significant therapeutic strategies to treat asthma. Studies have demonstrated that mitochondrial metabolism and mass were increased in ASM acutely isolated from remodeled bronchi of asthmatic patients. It was also reported that ASM mitochondrial biogenesis was necessary to maintain the metabolic demands of AR. Calcium (Ca2+) is a crucial signaling molecule that is particularly important for cellular remodeling, especially AR. In addition, Ca2+ signaling regulates mitochondrial biogenesis through Ca2+/Calmodulin Kinase (CaMK). Thus, establishing a mechanistic connection between mitochondrial biogenesis, Ca2+ signaling, and AR could lead to successful strategies for targeting AR in asthma Recently, the newly described mitochondrial sodium (Na+)/Ca2+ exchanger (NCLX) has emerged as a novel modulator of Ca2+ signaling and mitochondrial function and dysregulation of NCLX activity leads to disease. Therefore, I hypothesize that NCLX activity is crucial for AR during asthma through NCLX-mediated shuttling of mitochondrial Ca2+ signals into cytosolic microdomains to regulate mitochondrial biogenesis and metabolism. Here, I propose to understand the mechanism(s) by which NCLX mediates enhancement of ASM mitochondrial biogenesis and AR (Aim 1) and determine the role of NCLX in AR in vivo using smooth muscle-specific NCLX knockout mice and a model of asthma (Aim 2). This proposal will identify novel specific molecular targets for AR and asthma. The research of this F30 proposal serves as an integral part of a comprehensive and individualized training plan to allow Martin Johnson to excel towards his career as a physician-scientist. The Penn State College of Medicine will provide the adequate facilities, resources, and training to complete this training plan. Martin will be mentored by renowned smooth muscle and calcium signaling biologists and physician-scientists to guide him throughout his project. During the duration of this proposed training plan, Martin will contribute stellar first-author papers and present novel mechanistic knowledge at national/international meetings related to ASM remodeling and asthma. As experienced mentors, Drs. Mohamed Trebak and Donald Gill will serve as the sponsor and co- sponsor of Martin’s training plan and provide any necessary assistance to allow Martin to become a successful physician-scientist.

项目总结/摘要 哮喘，传统上被认为是一种慢性气道炎性疾病， 25.7每年有100万美国人。这种复杂疾病的发病机制现在不仅被认为是 由于炎症，但也由于气道的结构变化，称为气道重塑（AR）。 特别是，气道平滑肌（ASM）重塑已被证明会导致肺动脉压下降， 功能，有助于气道高反应性（AHR），并恶化哮喘症状。目前还 没有针对哮喘AR的靶向治疗。了解AR的分子机制可能会导致显著的 哮喘的治疗策略。 研究表明，急性分离的ASM线粒体代谢和质量增加 从哮喘病人重塑的支气管中提取也有报道称，ASM线粒体生物发生是 维持AR的代谢需求所必需的。钙（Ca 2+）是一种重要的信号分子， 对细胞重塑尤其是AR尤为重要。此外，Ca 2+信号调节线粒体 钙调蛋白激酶（CaMK）介导的生物合成。因此，建立一个机械连接之间 线粒体生物发生、Ca 2+信号和AR可能导致哮喘中靶向AR的成功策略 最近，新描述的线粒体钠（Na+）/Ca 2+交换器（NCLX）已成为一种新的 Ca 2+信号传导和线粒体功能的调节剂以及NCLX活性的失调导致疾病。 因此，我假设NCLX活性在哮喘期间通过NCLX介导的 线粒体Ca 2+信号进入胞质微区以调节线粒体生物发生和代谢。 在这里，我建议了解NCLX介导增强ASM线粒体的机制， 生物发生和AR（目的1），并使用平滑肌特异性NCLX确定NCLX在体内AR中的作用 基因敲除小鼠和哮喘模型（Aim 2）。该提案将确定AR的新的特异性分子靶点 和哮喘。 对F30提案的研究是全面和个性化培训的组成部分。 计划让马丁约翰逊成为一名出色的物理学家和科学家。宾夕法尼亚州立大学 医学部将提供足够的设施、资源和培训，以完成本培训计划。马丁将 由著名的平滑肌和钙信号生物学家和物理学家指导， 在整个项目中。在此期间提出的培训计划，马丁将贡献恒星第一作者 在与ASM重塑相关的国家/国际会议上发表论文并提出新的机械知识 和哮喘。作为经验丰富的导师，穆罕默德·特雷巴克博士和唐纳德·吉尔博士将担任赞助商和合作伙伴， 赞助马丁的培训计划，并提供任何必要的帮助，让马丁成为一个成功的 物理学家兼科学家