Mitochondrial Iron metabolism in Chronic Obstructive Pulmonary Disease

慢性阻塞性肺疾病中的线粒体铁代谢

基本信息

批准号：
9755475
负责人：
Suzanne M Cloonan
金额：
$ 24.9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-04 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9755475
关键词：
Academic Medical Centers Address Advisory Committees Affect Antioxidants Area Award Binding Biogenesis Biological Assay Biology Boston Bronchitis Cardiolipins Chronic Bronchitis Chronic Obstructive Airway Disease Cigarette smoke-induced emphysema Collaborations Complex Data Development Disease Disease susceptibility Electron Transport Environment Epithelial Cells Family Feedback Gene Expression Genes Genetic Genetic Predisposition to Disease Genomics Goals Human Image Immunoprecipitation Impairment In Vitro Inherited Interdisciplinary Study Iron Iron Chelating Agents Iron Regulatory Protein 2 Knowledge Laboratories Learning Light Lung Lung diseases Measures Medicine Mentors Mentorship Messenger RNA Methods Microarray Analysis Mitochondria Mitochondrial Proteins Molecular Mucociliary Clearance Mus Mutation New York Oxidative Stress Pathogenesis Pathologic Pathway interactions Patients Peer Review Peripheral Phase Play Predisposition Proteins Pulmonary Emphysema RNA Binding RNA immunoprecipitation sequencing Reagent Regulation Report (document)Reporting Research Research Personnel Resistance Respiratory physiology Response Elements Risk Factors Role Series Structure of parenchyma of lung Sulfur Susceptibility Gene Techniques Testing Therapeutic Therapeutic Agents Therapeutic Uses Time Training Transcript Translating Translational Repression Universities Untranslated Regions airway inflammation alpha 1-Antitrypsin Deficiency base biological adaptation to stress career career networking cigarette smoke cigarette smoke-induced cigarette smoke-induced COPD cytochrome c oxidase design experience experimental study exposure to cigarette smoke frataxin gene product genetic association imaging agent improved in vivo in vivo Model innovation interdisciplinary approach iron metabolism lung development lung imaging medical schools mitochondrial dysfunction mitochondrial metabolism next generation sequencing novel oxidation research facility respiratory response single photon emission computed tomography skills symptomatic improvement targeted treatment therapeutic target tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Project Summary. I aspire to become an independent investigator with a lab at a vibrant academic medical center and a leader in the study of mitochondrial dysfunction in lung disease, namely chronic obstructive pulmonary disease (COPD). To continue my progress towards this goal, I am proposing a multifaceted approach to address the specific hypothesis surrounding the deregulation of mitochondrial iron metabolism in the lung and the development of COPD, a timely and important topic. I posses the background, training and expertise in the key research areas for this application. I have carefully chosen an advisory committee composed of my mentor Prof. Augustine Choi, a world-renowned leader in pulmonary research and other accomplished investigators at Weill Cornell Medical College (WCMC) who will mentor and guide me throughout the time frame of this award. This award will provide critical support and time to continue my research under the mentorship of Prof. Choi at WCMC. Augustine's laboratory contains well-established facilities and expertise for carrying out pulmonary research and is an ideal environment for translating bench discoveries to disease-specific aspects of this project. It will also provide "protected" time to train in the ey research areas defined in this application specifically learning how to; 1) study mitochondrial iron metabolism 2) image mitochondria in the lung and 3) develop mitochondrial-based therapeutics for use in vivo. In the R00 phase of the award I will apply this training to better understand the pathogenesis of COPD and evaluate the efficacy of these methods for COPD therapeutics. The energetic dynamic environment of WCMC will provide me access to world-class research facilities, and allow me to expand my knowledge, skills and professional network. My collaborations within WCMC and outside including Columbia University Medical Center in New York, Harvard Medical School and Northeastern University in Boston will not only allow me to interact with a range of investigators with diverse skill sets, but will also allow me to presen and share my data with others to gain important peer-reviewed feedback. The projects and training proposed in this application along with the expertise and experience afforded by my advisory committee and collaborators will provide me with the trans-disciplinary skills and knowledge I need to develop as an independent investigator. In this proposal I seek to characterize further the functional role of the COPD susceptibility gene transcript IRP2 in the pathogenesis of cigarette smoke (CS)-induced COPD. I also wish to use IRP2 as a tool to investigate the role of mitochondrial metabolism in lung function and the susceptibility of the lung to cigarette smoke. I show that mice lacking IRP2 are protected from CS-induced bronchitis and emphysema and have altered responses to CS exposure. IRP2 recognizes and binds to iron response elements located in mRNA resulting in translational repression or stabilization. To identify novel IRP2 target transcripts in the lung I performed 1) microarray analysis of IRP2-/- mouse lungs and 2) RIP-Seq, specifically, immunoprecipitation of IRP2 from human bronchial epithelial cells followed by next generation sequencing of IRP2-bound RNA. Preliminary data from these experiments showed that IRP2 regulates transcripts important for mitochondrial iron metabolism and function in the lung. I compared these data with RNA-Seq data from the Lung Genomics Research Consortium, which included controls and patients with COPD. The same pathways identified by the IRP2 RIP-Seq and microarray were altered in COPD patients, further strengthening the association between IRP2, these pathways and the development of COPD. Based on this preliminary data, I hypothesize that IRP2 modulates pathways important for the response of the lung to cigarette smoke by regulating mitochondrial function. This hypothesis will be tested using the following aims: 1. Characterize the function of IRP2 in the response of mitochondria to CS exposure. 2. Determine the function of IRP2-regulated mitochondrial pathways in experimental COPD. 3. Determine mitochondrial-based approaches for COPD therapy. With a panel of novel reagents and assays including IRP2-/- mice, in vivo models for COPD, innovative mitochondrial-targeted therapeutics and novel real-time approaches to imaging the lung in vivo, this project proposes a multifaceted, interdisciplinary approach to characterize the mechanisms by which IRP2 regulates CS responses in the lung and how this plays a critical role in the pathogenesis of COPD. COPD remains a complex debilitating disease that encompasses a variety of pathologic conditions including emphysema and chronic bronchitis and affects approximately 15 million people in the USA. Few advances have been made to alleviate the bronchitis or emphysema associated with COPD with suboptimal therapeutic options mildly improving the symptoms of COPD rather than substantially modifying its course. Discoveries, techniques and observations made in these studies will contribute greatly to investigators of basic respiratory medicine in the COPD field and also to investigators in other fields related to mitochondrial iron-associated disorders. Most importantly these studies may also aid in the design of better therapeutic agents to target COPD and help reduce the burden of this lung disease on patients and their families.

描述（申请人提供）：项目摘要。我渴望成为一个充满活力的学术医学中心实验室的独立研究者，并且是肺部疾病线粒体功能障碍研究的领导者，即慢性阻塞性肺疾病（COPD）。为了继续朝着这个目标朝着这个目标迈进，我提出了一种多方面的方法，以解决围绕肺中线粒体铁代谢放松管制的特定假设，而COPD的发展是及时且重要的话题。我在此应用程序的关键研究领域中拥有背景，培训和专业知识。我仔细选择了一个由我的导师奥古斯丁·崔（Augustine Choi）教授组成的咨询委员会，奥古斯丁·崔（Augustine Choi）是世界知名的肺部研究领导者，以及威尔·康奈尔医学院（WCMC）的其他有成就的调查员，他们将在整个奖项的整个期限内指导和指导我。该奖项将为Choi教授在WCMC的指导下继续我的研究提供重要的支持和时间。奥古斯丁的实验室包含了公认的设施和专业知识，用于进行肺部研究，是将基准发现转化为该项目特定方面的理想环境。它还将提供“受保护”的时间在本应用程序中定义的EY研究领域进行培训。 1）研究线粒体铁代谢2）肺中的图像线粒体和3）开发基于线粒体的疗法用于体内。在奖励的R00阶段，我将应用此培训，以更好地了解COPD的发病机理，并评估这些方法对COPD治疗的疗效。 WCMC充满活力的动态环境将使我访问世界一流的研究设施，并让我扩大知识，技能和专业网络。我在WCMC和境外的合作包括纽约的哥伦比亚大学医学中心，哈佛医学院和波士顿的东北大学，不仅可以让我与一系列具有多种技能的调查员进行互动，而且还可以让我与其他人进行预言并分享我的数据，以获得重要的同行评估反馈。本申请中提出的项目和培训以及我的咨询委员会和合作者提供的专业知识和经验将为我提供我作为独立研究者所需的跨学科技能和知识。在此提案中，我试图进一步表征COPD敏感性基因转录本IRP2在香烟烟雾（CS）引起的COPD发病机理中的功能作用。我还希望使用IRP2作为研究线粒体代谢在肺功能以及肺对香烟烟雾的敏感性的作用的工具。我表明，缺乏IRP2的小鼠受到CS诱导的支气管炎和肺气肿的保护，并改变了对CS暴露的反应。 IRP2识别并与位于mRNA中的铁反应元件结合，从而导致翻译抑制或稳定。为了鉴定肺I进行的新型IRP2目标转录本进行1）IRP2 - / - 小鼠肺的微阵列分析和2）RIP-SEQ，特别是，从人支气管上皮细胞中对IRP2进行免疫沉淀，然后对IRP2-Bound-bound-bound-bound-bound-bound-bound rna进行下一代测序。这些实验的初步数据表明，IRP2调节对线粒体铁代谢和肺部功能重要的转录本。我将这些数据与来自肺基因组研究联盟的RNA-seq数据进行了比较，其中包括对照和COPD患者。 COPD患者改变了IRP2 RIP-SEQ和微阵列确定的相同途径，进一步加强了IRP2，这些途径和COPD发展之间的关联。基于此初步数据，我假设IRP2通过调节线粒体功能来调节对肺对香烟烟雾的反应很重要的途径。该假设将使用以下目的进行检验：1。表征IRP2在线粒体对CS暴露响应中的功能。 2。确定实验COPD中IRP2调节的线粒体途径的功能。 3。确定基于线粒体的COPD治疗方法。 With a panel of novel reagents and assays including IRP2-/- mice, in vivo models for COPD, innovative mitochondrial-targeted therapeutics and novel real-time approaches to imaging the lung in vivo, this project proposes a multifaceted, interdisciplinary approach to characterize the mechanisms by which IRP2 regulates CS responses in the lung and how this plays a critical role in the pathogenesis COPD。 COPD仍然是一种复杂的使人衰弱的疾病，包括多种病理状况，包括肺气肿和慢性支气管炎，并影响美国约1500万人。很少有进步能够减轻与COPD相关的支气管炎或肺气肿，并与次优的治疗选择轻度改善COPD的症状，而不是实质上改变其病程。这些研究中的发现，技术和观察结果将为COPD领域的基本呼吸医学研究者以及与线粒体铁相关疾病有关的其他领域的研究者做出巨大贡献。最重要的是，这些研究也可能有助于设计更好的治疗剂以瞄准COPD，并有助于减轻患者及其家人的肺部疾病负担。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Hepcidin Is Essential for Alveolar Macrophage Function and Is Disrupted by Smoke in a Murine Chronic Obstructive Pulmonary Disease Model.

DOI：
10.4049/jimmunol.1901284
发表时间：
2020-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Perez E;Baker JR;Di Giandomenico S;Kermani P;Parker J;Kim K;Yang J;Barnes PJ;Vaulont S;Scandura JM;Donnelly LE;Stout-Delgado H;Cloonan SM
通讯作者：
Cloonan SM

Smoking-induced iron dysregulation in the lung.