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

项目摘要/摘要 哮喘传统上被认为是一种慢性呼吸道炎症性疾病，影响 每年有2570万美国人。这种复杂疾病的发病机制现在不仅被认为是 由于炎症，但也由于呼吸道的结构变化，称为呼吸道重塑(AR)。 具体地说，已经证实，气道平滑肌(ASM)重塑导致肺功能下降。 功能，促进呼吸道高反应性(AHR)，并加重哮喘症状。目前，有 哮喘患者的AR没有靶向治疗。了解AR的分子机制可能导致显著的 治疗哮喘的治疗策略。 研究表明，急性分离的ASM线粒体代谢和质量增加。 来自哮喘患者的重塑的支气管。另据报道，ASM线粒体的生物发生是 维持AR的代谢需求所必需的。钙(钙)是一种重要的信号分子，它是 对细胞重塑尤其重要，尤其是AR。此外，钙信号调节线粒体 通过钙/钙调蛋白激酶(CaMK)的生物发生。因此，建立了一种机械连接 线粒体生物发生、钙信号和AR可能导致针对哮喘AR的成功策略 最近，线粒体钠(Na)/钙交换器(NCLX)作为一种新的 钙信号和线粒体功能的调节器以及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介导的穿梭在AR中起关键作用。 线粒体钙信号进入胞质微区，调节线粒体的生物发生和代谢。 在这里，我建议了解NCLX介导ASM线粒体增强的机制(S NCLX的生物发生与AR(目标1)及其在活体AR中的作用 基因敲除小鼠和哮喘模型(目标2)。这项提议将确定AR的新的特定分子靶点 还有哮喘。 对F30方案的研究是全面和个性化培训的组成部分 计划让马丁·约翰逊在他作为内科科学家的职业生涯中脱颖而出。宾夕法尼亚州立大学 医学将提供足够的设施、资源和培训来完成这一培训计划。马丁将会是 由著名的平滑肌和钙信号生物学家和内科科学家指导他 在他的整个项目中。在这项拟议的培训计划期间，马丁将为《明星第一作者》做出贡献。 在与ASM重塑相关的国内/国际会议上发表论文和介绍新的机制知识 还有哮喘。作为经验丰富的导师，Mohamed Trebak博士和Donald Gill博士将担任赞助商和联合 马丁培训计划的赞助商，并提供任何必要的帮助，使马丁成为一名成功的 医生兼科学家。

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.