The role of NFATc3 in altered hypoxic pulmonary vasoconstriction during acute lung injury

NFATc3 在急性肺损伤期间缺氧性肺血管收缩改变中的作用

• 批准号: 9751948
• 负责人: Dustin Fraidenburg
• 金额: $ 17.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751948
• 关键词: Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Animal Model; Area; Attenuated; Authorship; Blood; Blood Vessels; Calcineurin; Calcium; Calcium Channel; Career Mobility; Cell Nucleus; Cells; Collaborations; Data; Development; Disease; Down-Regulation; Environmental air flow; Epigenetic Process; Experimental Animal Model; Extramural Activities; Family member; Fostering; Functional disorder; Future; Gases; Gene Targeting; Genetic Transcription; Goals; Grant; Human; Hypoxemia; Hypoxia; Impairment; Inflammation; Inflammatory; Injections; Knowledge; Learning; Lung; Lung Inflammation; Lung diseases; Manuscripts; Mediating; Mentorship; Modification; Molecular Target; Morbidity - disease rate; Mus; Pathogenesis; Patients; Perfusion; Phosphoric Monoester Hydrolases; Physicians; Physiological; Play; Preparation; Process; Protein Dephosphorylation; Proteins; Publications; Pulmonary artery structure; Research; Research Activity; Research Methodology; Research Personnel; Research Project Grants; Research Proposals; Risk Factors; Role; Scientist; Sepsis; Signal Transduction; Smooth Muscle Myocytes; Structure; Structure of parenchyma of lung; T-Cell Activation; Technical Expertise; Testing; Time; Training; Vascular Diseases; Vascular Smooth Muscle; Vascular blood supply; Work; Writing; base; career; in vivo; inorganic phosphate; lung injury; mortality; negative affect; novel; nuclear factors of activated T-cells; peer; protein expression; respiratory; skills; transcription factor; transcription factor NF-AT c3; vasoconstriction

Lung inflammation and hypoxemia are major risk factors for mortality in acute respiratory distress syndrome, a disorder characterized by mortality that by some estimates can exceed 40%. Sepsis, a severe inflammatory disorder, is the primary cause of morbidity and mortality in these patients. Impaired gas exchange and hypoxemia define this severe respiratory illness and matching of ventilation and perfusion in the lung microenvironment is crucial for adequate gas exchange. Impaired hypoxic pulmonary vasoconstriction (HPV) results in ventilation and perfusion mismatching leading to hypoxemia and impaired HPV has been implicated in multiple pulmonary diseases associated with inflammation, including sepsis and acute lung injury. The current proposal focuses on the role of nuclear factor of activated T-cells (NFAT) in impaired hypoxic pulmonary vasoconstriction (HPV) during acute lung injury and inflammation. NFAT is a transcription factor that translocates to the nucleus after phosphate cleavage by calcineurin, as calcium dependent phosphatase, where it transcriptionally regulates numerous gene targets. NFAT has been implicated in multiple inflammatory disease processes including experimental animal models of sepsis and ALI. TRPC channels are an essential factor in intracellular calcium influx and signaling that is crucial for pulmonary vasoreactivity. Our preliminary data suggests that LPS-induced lung injury leads to NFAT activation and impaired hypoxic pulmonary vasoconstriction, potentially due to downregulation of TRPC channels. We hypothesize that acute lung inflammation causes impaired HPV and downregulated TRPC channel expression and function leading to hypoxemia in ARDS patients. The inflammation- mediated TRPC channel downregulation is due to NFAT-mediated epigenetic modifications which can be targeted in experimental animal models and in vivo preparations. We will use specific aims in order to define this relationship. In Aim 1 we will determine the effects of lung inflammation and NFAT activation on pulmonary artery smooth muscle cells and pulmonary vasoreactivity. In Aim 2 we will determine the epigenetic mechanisms responsible for changes in the PASMC and pulmonary vasoreactivity due to NFAT activation. In Aim 3 we will determine the effects of inflammation, NFAT activation, and epigenetic modifications in a novel in vivo mouse preparation. In addition to the research proposal, a detailed training plan has been proposed in order to facilitate the development of a successful career as a physician-scientist. We describe how mentorship will foster skills in research methods, writing development, and career advancement through protected research time, didactic learning, peer recognition, intramural and extramural training, authorship, collaboration and future grant development. We have proposed a graded structure in which research activities which represent at least 75% time commitment initially have a strong emphasis on course work and learning opportunities which gradually evolves into more time spent on the research project, manuscript publication, and R01 development. Our long-term goals are to define the mechanisms of impaired HPV in lung inflammation in order to identify novel molecular targets to enhance V/Q matching and gas exchange in the lung. With this proposal I hope to strengthen my knowledge and technical skills in pulmonary vascular disease research in order to facilitate my development as an independent investigator and successful physician-scientist.

肺部炎症和低氧血症是急性呼吸道疾病死亡的主要危险因素 痛苦综合征，一种以死亡率为特征的疾病，据估计， 百分之四十脓毒症是一种严重的炎症性疾病，是糖尿病患者发病和死亡的主要原因。 这些病人。气体交换受损和低氧血症定义了这种严重的呼吸道疾病， 肺微环境中通气和灌注的匹配对于充足的气体至关重要 交易所缺氧性肺血管收缩（HPV）受损导致通气和 灌注不匹配导致低氧血症和受损的HPV已涉及多种 与炎症相关的肺部疾病，包括败血症和急性肺损伤。 目前的建议集中在活化T细胞核因子（NFAT）在 在急性肺损伤和炎症过程中缺氧性肺血管收缩（HPV）受损。 NFAT是一种转录因子，其在磷酸裂解后易位至细胞核， 钙调神经磷酸酶，作为钙依赖性磷酸酶，它在转录上调节许多 基因靶点NFAT与多种炎性疾病过程有关，包括 脓毒症和ALI的实验动物模型。TRPC渠道是一个重要因素， 细胞内钙内流和信号传导对肺血管反应性至关重要。我们 初步数据表明，LPS诱导的肺损伤导致NFAT激活和受损， 缺氧性肺血管收缩，可能是由于TRPC通道下调。我们 假设急性肺部炎症导致HPV受损和TRPC下调 通道的表达和功能导致ARDS患者低氧血症。炎症- NFAT介导的表观遗传修饰导致TRPC通道下调 其可以在实验动物模型和体内制剂中靶向。 我们将使用特定的目标来定义这种关系。在目标1中，我们将确定 肺炎症和NFAT激活对肺动脉平滑肌细胞的影响， 肺血管反应性在目标2中，我们将确定表观遗传机制， 由于NFAT激活导致的PASMC和肺血管反应性的变化。在目标3中， 确定炎症的影响，NFAT激活，和表观遗传修饰在一个新的 体内小鼠制备。 除了研究建议外，还提出了详细的培训计划，以便 促进作为一名物理学家-科学家的成功职业发展。我们描述了如何 导师制将培养研究方法、写作发展和职业发展方面的技能 通过保护研究时间，教学式学习，同行认可，校内和校外 培训、著作权、合作和未来的赠款发展。我们提出了一个分级的 在这种结构中，研究活动最初至少占75%的时间承诺， 非常重视课程工作和学习机会，逐渐演变为 更多的时间花在研究项目、手稿出版和R 01开发上。 我们的长期目标是确定HPV在肺部炎症中受损的机制， 为了确定新的分子靶点，以增强V/Q匹配和气体交换， 肺。通过这个建议，我希望加强我的知识和技能，肺 血管疾病研究，以促进我作为一个独立的研究者的发展 成功的物理学家兼科学家