Mechanisms and clinical relevance of hypercapnia-induced skeletal muscle atrophy in Chronic Obstructive Pulmonary Disease (COPD)

慢性阻塞性肺疾病（COPD）中高碳酸血症引起的骨骼肌萎缩的机制和临床相关性

• 批准号: 9923744
• 负责人: Adolfo Ariel Jaitovich
• 金额: $ 15.47万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923744
• 关键词: Academic Training; Anabolism; Animal Model; Animals; Area; Argentine; Atrophic; Award; Basic Science; Biology; Blood; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Carbon Dioxide; Cardiovascular system; Catabolism; Cell physiology; Cellular biology; Chronic Obstructive Airway Disease; Clinical; Collaborations; Complex; Critical Care; Data; Disease model; Down-Regulation; Environment; Event; Exposure to; Faculty; Feedback; Fellowship; Fostering; Funding; Genes; Genetically Modified Animals; Goals; Head; Hypercapnia; Immigrant; Impairment; In Vitro; Institution; Interleukin-13; Interstitial Collagenase; Laboratories; Lead; Ligase; Lung; Lung diseases; Mediating; Medical center; Medicine; Mentored Research Scientist Development Award; Mentorship; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscular Atrophy; National Research Service Awards; Nobel Prize; Nuclear Translocation; Outcome; Partial Pressure; Pathology; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physicians; Population; Positioning Attribute; Process; Proteins; Proteolysis; Publishing; Pulmonary Emphysema; Quality of life; Regulation; Reporting; Research; Research Personnel; Research Training; Resources; Ribosomes; Rodent; STK11 gene; Science; Scientist; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Spain; Surface; Testing; Time; Training; Training Support; Transcription Initiation; Transgenic Animals; Transgenic Mice; Translational Research; Translations; Universities; Work; base; career; clinically relevant; collagenase; community college; emotional distress; experience; extracellular; in vivo; innovation; insight; interest; loss of function; medical schools; mitochondrial dysfunction; mortality; mouse model; multicatalytic endopeptidase complex; mutant; neuromuscular; novel; outcome forecast; prevent; professor; programs; protein degradation; rRNA Precursor; recruit; release of sequestered calcium ion into cytoplasm; response; skeletal muscle wasting; tool; transcription factor; transcriptional intermediary factor 1

PROJECT SUMMARY Candidate: Dr. Jaitovich academic training, research experience and intense drive place him in an excellent position for a successful career as an independent physician/scientist. Dr. Jaitovich is an Argentinean immigrant who has developed extensive expertise in the field of protein turnover and degradation, and has worked in collaboration with Nobel Prize- winner Aaron Ciechanover, which reflects his remarkable standard of training in that field. In addition, he has been recruited as Assistant Professor of Pulmonary and Critical Care Medicine at Albany Medical College based on feedback he received upon submission of his NRSA award. At that time, and due to his strong interest in skeletal muscle atrophy in the context of pulmonary diseases, he was recommended to find an institution with higher expertise in muscle biology. He has recently established collaborations with two world experts in animal models of emphysema: Drs. Jack Elias and Jeanine D’Armiento, who will provide him the opportunity to test his hypotheses in complementary transgenic animals with previously developed lung disease. Dr. Jaitovich intends to pursue a career in academic medicine with a strong commitment to innovative basic and translational research. He has used his fellowship training to gain expertise in cell biology and in murine models of disease. Supported by this award, he will establish a novel niche within the area of muscle atrophy in the context of advanced pulmonary disease. Training supported by this K01 award will allow him to pursue his career as an independent investigator. Environment Mentorship: The Division of Pulmonary and Critical Care Medicine and the Center for Cardiovascular Sciences at the Albany Medical College are committed to fostering the academic careers of outstanding junior faculty like Dr. Jaitovich. Drs. Harold Singer, Yong-Xiao Wang and Dale Tang are well-funded, established investigators with a long track record of training. Their laboratories have the tools and resources required to complete the proposed studies, which have been specifically crafted to develop a novel and innovative research program independent from their own, and which will facilitate Dr. Jaitovich career. In addition, Dr. Jaitovich will receive full collaboration from Dr. Jacob Sznajder (Northwestern University), who is an expert in CO2-mediated cell signaling; Dr. Jack Elias (Brown University), who is an expert in animal models of emphysema/COPD; Dr. Jeanine D’Armiento (Columbia University), who is also an expert in animal models of emphysema and has described one of the first transgenic animals of that kind (lung MMP1+/- expression); Dr. Gustavo Nader (Penn State University), who has advanced expertise in regulation of anabolism in skeletal muscle; Dr. Esther Barreiro (Universitat Pompeu Fabra, Barcelona), a leading scientist in the field of COPD- associated muscle atrophy; and Dr. Jiang Qian (Albany Medical Center), who is the head of the neuromuscular core at the Department of Pathology of AMC. Environment: Dr. Jaitovich will conduct his research training in the Division of Pulmonary and Critical Care Medicine and the Center for Cardiovascular Sciences at the Albany Medical College (AMC). Additionally, he will have off-site collaboration from Northwestern University, Brown University, Columbia University, Penn State University, and Universitat Pompeu Fabra (Spain). Strong collaborations between the different federally funded investigators in this institution combined with their interactions with investigators in the AMC community and around the world provide an ideal environment for Dr. Jaitovich to develop an independent research program. Research: High CO2 in the blood or hypercapnia is common in patients with chronic obstructive pulmonary disease (COPD). These patients frequently develop skeletal muscle atrophy. Both hypercapnia and skeletal muscle atrophy are independent predictors of worse outcome in these populations. We recently reported that exposure to high CO2 leads to muscle atrophy and anabolic suppression in vitro and in vivo. This process occurs via CO2-induced AMPK phosphorylation, which targets the transcription factor FoxO3a, which (after nuclear translocation) induces the expression of the muscle-specific E-3 ligase MuRF1. These events lead to proteasome-mediated protein degradation and muscle atrophy. Here, we plan to expand our mechanistic insight and determine how hypercapnia causally leads to AMPK activation and net muscle loss; and evaluate these processes in skeletal muscles from emphysematous mice. Specific Aim 1: To determine the mechanism leading to AMPK phosphorylation under CO2 stimulation. We will explore the upstream signals that mediate high CO2-induced AMPK phosphorylation with particular emphasis to the distinct influence of calcium currents and mitochondrial dysfunction. To do that, we will use gain and loss-of-function approaches to determine the effect of CO2 on muscle cell signaling. Specific Aim 2: To determine whether hypercapnia leads to an AMPK-dependent down-regulation of skeletal muscle anabolism through phosphorylation of TIF-1A. We will investigate if high CO2-induced down regulation of 45s pre-rRNA occurs through the AMPKα1-mediated phosphorylation of TIF-1A and decreased TIF-1A/TBP- SL1 interaction, precluding the assembly of functional transcription initiation complexes. Specific Aim 3: To determine if genetically modified animals that develop pulmonary emphysema (IL-13 and MMP1+/-) display accelerated skeletal muscle atrophy under high CO2 compared to wild type littermates. We will also explore the relevance of the AMPK-MuRF1 axis in that process; and the rate of muscle anabolism in normo and hypercapnia in both wild type and transgenic mice.

项目概要 候选人：Jaitovich 博士的学术训练、研究经验和强烈的动力使他处于一个绝佳的职位： 作为一名独立医生/科学家的成功职业生涯。 Jaitovich 博士是一位阿根廷移民，他开发了 在蛋白质周转和降解领域拥有丰富的专业知识，并与诺贝尔奖合作- 冠军亚伦·切哈诺沃 (Aaron Ciechanover)，这反映了他在该领域的卓越训练水平。此外，他还曾 根据反馈被聘为奥尔巴尼医学院肺科和重症监护医学助理教授 他在提交 NRSA 奖项后获得了该奖。当时，由于他对骨骼肌萎缩的浓厚兴趣， 在肺部疾病的背景下，他被建议寻找一家在肌肉生物学方面具有更高专业知识的机构。他 最近与肺气肿动物模型领域的两位世界专家建立了合作：Drs.杰克·埃利亚斯和 Jeanine D’Armiento，她将为他提供在互补转基因动物中检验他的假设的机会 以前患有肺部疾病。 Jaitovich 博士打算在学术医学领域从事具有强大实力的职业生涯 致力于创新基础和转化研究。他利用奖学金培训获得了细胞方面的专业知识 生物学和小鼠疾病模型。在该奖项的支持下，他将在以下领域建立一个新的利基市场： 晚期肺部疾病背景下的肌肉萎缩。 K01 奖项支持的培训将使他能够 作为一名独立调查员继续他的职业生涯。 环境 指导：肺科和重症医学科以及心血管科学中心 奥尔巴尼医学院致力于培养像 Jaitovich 博士这样的杰出初级教师的学术生涯。 博士。哈罗德·辛格 (Harold Singer)、王永晓 (Yong-Xiao Wang) 和唐戴尔 (Dale Tang) 是资金雄厚、实力雄厚的调查员，在 训练。他们的实验室拥有完成拟议研究所需的工具和资源，这些研究已 专门设计用于开发独立于自己的新颖且创新的研究计划，这将 促进贾伊托维奇博士的职业生涯。此外，Jaitovich 博士将得到 Jacob Sznajder 博士的全面合作 （西北大学），二氧化碳介导的细胞信号传导专家； Jack Elias 博士（布朗大学） 肺气肿/慢性阻塞性肺病动物模型专家； Jeanine D’Armiento 博士（哥伦比亚大学），也是该领域的专家 肺气肿动物模型，并描述了该类型的第一个转基因动物（肺 MMP1+/- 表达）; Gustavo Nader 博士（宾夕法尼亚州立大学）在合成代谢调节方面拥有先进的专业知识 骨骼肌； Esther Barreiro 博士（巴塞罗那庞培法布拉大学），慢性阻塞性肺病领域的领先科学家 相关的肌肉萎缩；以及江谦博士（奥尔巴尼医学中心），他是该中心神经肌肉核心的负责人 AMC 病理科。 环境：Jaitovich 博士将在肺科和重症监护医学科进行研究培训 奥尔巴尼医学院 (AMC) 心血管科学中心。此外，他还将在场外 西北大学、布朗大学、哥伦比亚大学、宾夕法尼亚州立大学和大学的合作 庞培·法布拉（西班牙）。该机构不同联邦资助的调查人员之间的密切合作 结合他们与 AMC 社区和世界各地调查人员的互动，提供了一个理想的 Jaitovich 博士开发独立研究项目的环境。 研究：血液中高二氧化碳或高碳酸血症在慢性阻塞性肺病患者中很常见 （慢性阻塞性肺病）。这些患者经常出现骨骼肌萎缩。高碳酸血症和骨骼肌萎缩都是 这些人群中更糟糕结果的独立预测因素。我们最近报道称，接触高二氧化碳会导致 体外和体内肌肉萎缩和合成代谢抑制。该过程通过 CO2 诱导的 AMPK 发生 磷酸化，其目标是转录因子 FoxO3a，（核转位后）诱导表达 肌肉特异性 E-3 连接酶 MuRF1。这些事件导致蛋白酶体介导的蛋白质降解和肌肉 萎缩。在这里，我们计划扩展我们的机制见解并确定高碳酸血症如何导致 AMPK 激活和净肌肉损失；并评估肺气肿小鼠骨骼肌中的这些过程。 具体目标 1：确定 CO2 刺激下 AMPK 磷酸化的机制。我们将探索 介导高 CO2 诱导的 AMPK 磷酸化的上游信号，特别强调独特的影响 钙电流和线粒体功能障碍。为此，我们将使用增益和功能丧失方法来 确定 CO2 对肌肉细胞信号传导的影响。 具体目标 2：确定高碳酸血症是否会导致骨骼肌 AMPK 依赖性下调 通过 TIF-1A 磷酸化进行合成代谢。我们将研究高 CO2 是否诱导 45s pre-rRNA 下调 通过 AMPKα1 介导的 TIF-1A 磷酸化和减少 TIF-1A/TBP-SL1 相互作用而发生，从而阻止 功能性转录起始复合物的组装。 具体目标 3：确定转基因动物是否会出现肺气肿（IL-13 和 MMP1+/-） 与野生型同窝小鼠相比，在高 CO2 条件下骨骼肌萎缩加速。我们还将探索 AMPK-MuRF1 轴在此过程中的相关性；以及正常和高碳酸血症两种情况下的肌肉合成代谢率 野生型和转基因小鼠。