Smoke induced alterations in ion channel function

烟雾引起离子通道功能的改变

• 批准号: 9264009
• 负责人: Monica Prasad Goldklang
• 金额: $ 16.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264009
• 关键词: Advisory Committees; Animal Model; Area; Arrhythmia; Asthma; Biology; Calcium; Cause of Death; Cell membrane; Cells; Chronic Obstructive Airway Disease; Collaborations; Complex; Coupled; Critical Care; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Electrophysiology (science); Evaluation; FKBP1B gene; Functional disorder; Funding; Gelatinase B; Genetic Transcription; Goals; Grant; Heart failure; Impaired cognition; Inflammatory; Injury; Investigation; Ion Channel; K-Series Research Career Programs; Knock-in Mouse; Knockout Mice; Learning Skill; Lung; Lung diseases; Macrophage Activation; Matrix Metalloproteinases; Mechanics; Mediating; Mentors; Methods; Modeling; Modification; Molecular; Mus; Muscle relaxation phase; Mutant Strains Mice; Oxidative Stress; Pathogenesis; Pathologic; Peptide Hydrolases; Phenotype; Physicians; Play; Post-Translational Protein Processing; Potassium; Probability; Publications; Pulmonary Emphysema; Relaxation; Reporting; Research; Research Personnel; Research Project Grants; Research Training; Role; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Scheme; Signal Transduction; Smoke; Smoking; Smooth Muscle; Smooth Muscle Myocytes; Stress; Structure; Testing; Time; Tissues; Training; Transgenic Organisms; United States; United States National Institutes of Health; Up-Regulation; Work; Writing; airway hyperresponsiveness; airway inflammation; career development; cell type; cigarette smoke-induced; large-conductance calcium-activated potassium channels; lung injury; mRNA Expression; macrophage; member; morphometry; mouse model; multidisciplinary; new therapeutic target; novel; oxidation; prevent; public health relevance; response; response to injury; rottlerin; skills; translational scientist; voltage

 DESCRIPTION (provided by applicant): This proposed K08 Mentored Career Development Award will enable me to develop into an established and independent researcher with expertise on the role of ion channels in smoking related lung disease. I am a fully trained pulmonary and critical care physician as well as a basic and translational researcher with a long-term goal of understanding the implications of ion channel dysfunction in smoking related lung disease. However, further career development and research training is necessary for me to reach this goal. I have a long- standing, productive relationship with my mentor, Dr. Jeanine D'Armiento, a well-established researcher in matrix metalloproteinase biology and smoke related lung disease. In collaboration with Dr. Andrew Marks, co- mentor of this proposal, and Dr. Steven Marx, a member of my advisory committee, we recently demonstrated that activation of large conductance, voltage and Ca2+ activated potassium (BK) channels with the compound rottlerin reduces airway hyper responsiveness in two murine models of asthma. The present proposal extends this successful collaboration and examines alterations in BK channel and ryanodine receptor (RyR) activity in smoke exposure conditions. We have identified post-translational modifications of RyR2 and potential BK channel mediated alterations in matrix metalloproteinase expression in smoke exposure, and seek to determine the mechanisms underlying these interesting findings. Through the use of unique transgenic and knock-in mice, we will explore the role of BK channels and implications of post-transcriptional RyR2 modifications in destructive lung injury. I will work with a multidisciplinary advisory committee o established NIH investigators (Dr. D'Armiento, Dr. Marks, Dr. Marx, Dr. Charles Emala and Dr. Jahar Bhattacharya) to help me attain the goals of (1) utilizing unique animal models to understand the mechanisms of lung destruction; (2) obtaining training in electrophysiology methods to investigate smoke-induced cellular dysfunction; and (3) learning skills for research presentations, publications and effective grant writing for obtaining independent funding. I will use the skills acquired during this mentored research project to further my understanding of ion channels in destructive lung disease in the hope of identifying novel targets for new therapies.

 描述（由适用提供）：拟议的K08指导职业发展奖将使我能够发展成为一位知识渊博的独立研究人员，并在离子渠道在吸烟相关的肺部疾病中的作用方面具有专家。我是一位受过全面训练的肺和重症监护身体，也是一位基本和翻译的研究人员，其长期目标是了解离子通道功能障碍在与吸烟相关的肺部疾病中的影响。但是，对于我来说，进一步的职业发展和研究培训是必须实现这一目标的。我与我的心态长期存在的产品关系Jeanine D'Ariento博士是一位成熟的基质金属蛋白酶生物学和与烟有关的肺部疾病的良好研究员。该提案的同事安德鲁·马克斯（Andrew Marks）和我的咨询委员会成员史蒂文·马克思（Steven Marx）博士合作，我们最近证明，激活大型电导率，电压和CA2+活化钾（BK）频道（BK）频道与复合Rottlerin的激活降低了两种高鼠类欲望的鼠模型中的气道。本提案扩展了BK通道和Ryanodine受体（RYR）活性在烟雾暴露条件下的成功合作和检查改变。我们已经确定了RYR2的翻译后修饰和潜在的BK通道介导的烟雾蛋白酶表达中烟雾蛋白酶表达的变化，并寻求确定这些有趣发现的机制。通过使用独特的转基因和敲门小鼠，我们将探讨BK通道的作用以及转录后RYR2修饰在破坏性肺损伤中的影响。我将与跨学科的咨询委员会o合作o成立的NIH调查人员（D'Arimiento博士，马克斯博士，马克思博士，查尔斯·埃玛拉博士和Jahar Bhattacharya博士），以帮助我实现（1）实现独特的动物模型的目标，以了解肺部破坏的机制； （2）获得电生理方法的培训，以研究烟雾诱导的细胞功能障碍； （3）研究演示文稿，出版物和有效的赠款写作技巧，以获得独立资金。我将利用该指导研究项目中获得的技能来进一步了解破坏性肺部疾病中的离子渠道，以期确定新疗法的新靶标。