Role of Non-muscle MLCK in Neutrophil-mediated Acute Lung Injury

非肌肉 MLCK 在中性粒细胞介导的急性肺损伤中的作用

• 批准号: 7795922
• 负责人: Jingsong Xu
• 金额: $ 38.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795922
• 关键词: Actins; Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affinity; Avidity; Blood Vessels; Calcium; Calcium Signaling; Cell-Matrix Junction; Cytoskeleton; DNA Sequence Rearrangement; Data; Development; Endothelial Cells; Endothelium; Equilibrium; Feedback; Figs - dietary; Generations; Goals; Hydrogen Peroxide; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Integrins; Link; Lipopolysaccharides; Lung; Lung Inflammation; Lung diseases; MYLK gene; Mediating; Modeling; Molecular; Mus; Muscle; Myosin Light Chain Kinase; Myosin Light Chains; Myosin Type II; NADPH Oxidase; Neutrophil Activation; Oxidants; Pathogenesis; Pathway interactions; Permeability; Play; Prevention; Production; Protein Isoforms; Protein Kinase; Role; Signal Pathway; Signal Transduction; Site; Staging; TLR4 gene; Testing; Tissues; antimicrobial; base; cell motility; in vivo; killings; lung injury; microbial; migration; neutrophil; non-muscle myosin; novel; polymerization; protein-tyrosine kinase c-src; public health relevance; research study; src-Family Kinases; sulfated glycoprotein 2

DESCRIPTION (provided by applicant): The non-muscle myosin light chain kinase (MLCK) isoform contributes to the mechanism of increased vascular endothelial permeability in lipopolysaccharide (LPS) induced model of inflammatory lung injury, the primary cause of the acute respiratory distress syndrome (ARDS). However, the role of MLCK in the anti-microbial activity of neutrophils remains poorly understood. Based on our preliminary data, we will test the hypothesis that MLCK regulates neutrophil anti-microbial functions including cell attachment, motility, and oxidant generation. The proposed studies have the following specific aims: i) to dissect the myosin light chain (MLC) independent pathway of non-muscle MLCK that is required for the full activation of (2 integrins via the tyrosine kinases Src and Pyk2 and that in turn mediate neutrophil transmigration; ii) to determine the role of non-muscle MLCK in NADPH oxidase mediated oxidant production and to identify a potentially critical positive feedback loop between oxidant triggered Ca2+ signaling and MLCK activity; and iii) to address the role of LPS activated TLR4 signaling in the mechanism of MLCK activation via an ERK-dependent pathway. In these studies, we will identify the MLCK-regulated signaling pathways that mediate neutrophil transmigration and oxidant production, which in turn are crucial in the mechanism of acute lung injury. Our goal is to understand the molecular mechanisms of the non-muscle MLCK-mediated activation of neutrophils and its role in the genesis of the lung inflammatory response. We hope that through the understanding of the novel function of this MLCK isoform, more effective strategies will be developed for the prevention and treatment of lung inflammation and the resultant injury. PUBLIC HEALTH RELEVANCE: We propose to study the role of a protein kinase, non-muscle myosin light chain kinase (MLCK) in bacterial induced inflammatory lung injury, the primary cause of the acute respiratory distress syndrome (ARDS). We hope that through the understanding of the novel function of this MLCK isoform, more effective strategies will be developed for the prevention and treatment of lung inflammation and the resultant injury.

描述（由申请人提供）：非肌肉肌球蛋白轻链激酶（MLCK）同工型有助于脂肪多糖（LPS）诱导的炎症性肺损伤模型中血管内皮渗透性增加的机制，这是急性呼吸遇险综合征（ARDS）的主要原因。然而，MLCK在中性粒细胞的抗菌活性中的作用仍然很少了解。根据我们的初步数据，我们将测试MLCK调节中性粒细胞抗微生物功能的假设，包括细胞附着，运动性和氧化剂产生。拟议的研究具有以下具体目的：i）解剖非肌肉蛋白光链（MLC）非肌肉MLCK的独立途径，这是完全激活（通过酪氨酸激酶SRC和PYK2的2个整合素的完全激活所必需的），这反过来又介导了中性粒细胞迁移；氧化剂触发Ca2+​​信号传导和MLCK活性之间的正反馈回路； iii）解决LPS激活的TLR4信号在通过ERK依赖性途径激活MLCK激活机理中的作用。在这些研究中，我们将确定MLCK调节的信号传导途径，这些信号通路介导中性粒细胞转移和氧化剂的产生，而这对于急性肺损伤机制至关重要。我们的目标是了解非肌肉MLCK介导的中性粒细胞激活的分子机制及其在肺炎症反应的起源中的作用。我们希望通过了解这种MLCK同工型的新功能，将制定更有效的策略来预防和治疗肺部炎症和由此导致的损伤。公共卫生相关性：我们建议研究蛋白激酶，非肌肉肌球蛋白轻链激酶（MLCK）在细菌诱导的炎症性肺损伤中的作用，这是急性呼吸遇险综合征（ARDS）的主要原因。我们希望通过了解这种MLCK同工型的新功能，将制定更有效的策略来预防和治疗肺部炎症和由此导致的损伤。