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

项目总结 应聘者：Jaitovich博士的学术培训、研究经验和强烈的动力使他处于一个绝佳的位置 作为一名独立的医生/科学家取得成功的职业生涯。Jaitovich博士是一名阿根廷移民，他的 在蛋白质周转和降解领域拥有广泛的专业知识，并与诺贝尔奖合作- 冠军亚伦·切哈诺弗，这反映了他在这一领域的卓越训练水平。此外，他一直被 根据反馈招聘奥尔巴尼医学院肺部和重症监护医学助理教授 他在提交他的NRSA奖时收到了。当时，由于他对骨骼肌萎缩有浓厚的兴趣 在肺部疾病的背景下，他被建议寻找在肌肉生物学方面拥有更高专业知识的机构。他 最近与两位肺气肿动物模型方面的世界专家建立了合作关系：Jack Elias博士和 Jeanine D‘Armiento，他将为他提供机会，在互补的转基因动物中测试他的假设 以前患过肺部疾病。Jaitovich博士打算在学术医学领域追求事业，拥有强大的 致力于创新的基础研究和翻译研究。他利用他的奖学金训练获得了细胞方面的专业知识。 在生物学和小鼠疾病模型中。在这个奖项的支持下，他将在以下领域建立一个新的利基市场 在晚期肺部疾病的背景下肌肉萎缩。这项K01奖项支持的培训将使他能够 追求独立调查员的职业生涯。 环境 指导：肺和重症监护医学部和心血管科学中心 奥尔巴尼医学院致力于培养像Jaitovich博士这样优秀的初级教员的学术生涯。 Harold Singer博士、王永晓博士和Dale Tang博士都是资金雄厚、经验丰富的调查人员，他们在 训练。他们的实验室拥有完成拟议研究所需的工具和资源，这些研究已经 专门制定了一项独立于自己的新颖和创新的研究计划，这将 促进Jaitovich博士的职业生涯。此外，贾伊托维奇博士将得到雅各布·斯纳伊德博士的全力合作 (西北大学)，他是二氧化碳介导的细胞信号传递方面的专家；Jack Elias博士(布朗大学)，他是 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)，他也是 肺气肿的动物模型，并描述了这种类型的首批转基因动物之一(肺MMP1+/- 表达)；Gustavo Nader博士(宾夕法尼亚州立大学)，他在合成代谢调节方面拥有高级专业知识 骨骼肌；埃丝特·巴雷罗博士(巴塞罗那蓬佩法布拉大学)，慢阻肺领域的领先科学家- 相关肌肉萎缩；以及姜倩博士(奥尔巴尼医学中心)，他是 美国医学会病理学系。 环境：Jaitovich博士将在肺和重症监护医学部进行研究培训 奥尔巴尼医学院(AMC)心血管科学中心。此外，他还将在场外 来自西北大学、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 庞贝·法布拉(西班牙)。这个机构中不同的联邦资助的调查人员之间的密切合作 结合他们与AMC社区和世界各地的调查人员的互动，提供了一个理想的 为Jaitovich博士开发独立研究计划提供了环境。 研究：慢性阻塞性肺病患者血液中二氧化碳含量高或高碳酸血症常见 (COPD)。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。我们最近报告说，暴露在高二氧化碳环境中会导致 体内外对肌肉萎缩和合成代谢抑制的作用。这一过程通过二氧化碳诱导的AMPK发生 以转录因子FOXO3a为靶标的磷酸化，在核转位后诱导表达 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械洞察力，并确定高碳酸血症是如何导致AMPK的 在肺气肿小鼠的骨骼肌中评估这些过程。 具体目的1：探讨二氧化碳刺激下AMPK磷酸化的机制。我们将探索 介导二氧化碳诱导的AMPK高磷酸化的上游信号，特别强调明显的影响 钙电流和线粒体功能障碍。要做到这一点，我们将使用收益和函数损失方法来 确定二氧化碳对肌肉细胞信号的影响。 特定目标2：确定高碳酸血症是否导致依赖AMPK的骨骼肌下调 通过TIF-1A的磷酸化进行合成代谢。我们将研究高二氧化碳是否会导致45S Pre-rRNA下调 通过AMPKα1介导的TIF-1A的磷酸化和减少TIF-1A/TBP-SL1的相互作用而发生，排除 功能转录起始复合体的组装。 具体目标3：确定患有肺气肿(IL-13和MMP1+/-)的转基因动物 与野生型窝种相比，在高二氧化碳条件下表现出加速的骨骼肌萎缩。我们还将探索 AMPK-MuRF1轴在这一过程中的相关性；正常和高碳酸血症患者的肌肉合成代谢率 野生型和转基因小鼠。

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.