Genetics, Epigenetics, and Post-translational Modifications and the Development of Ventilator Induced Lung Injury (VILI)

遗传学、表观遗传学和翻译后修饰以及呼吸机所致肺损伤 (VILI) 的发生

• 批准号: 10455906
• 负责人: Stephen M Black
• 金额: $ 208.08万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-23 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455906
• 关键词: Genetics; Epigenetics; Post; translational; Modifications

PROGRAM SUMMARY Mechanical ventilation, a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS), also creates excessive mechanical stress that augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The pathobiology of VILI and ARDS share many inflammatory features including increases in lung vascular permeability due to loss of endothelial cell (EC) barrier integrity. Insights into VILI pathobiology have been incremental with no viable therapies realized. This PPG intensely focuses on increasing our understanding of: i) the transcription factors that relay the effects of excessive mechanical stress; ii) the molecular signaling pathways that lead to EC injury, including initial activation of a mechanosensitive Ca2+-regulatory receptor, transient receptor potential cation channel subfamily V member 4 (TRPV4); iii) post translational modifications (PTMs) that influence key signaling pathways involved in VILI responses; iv) genetic and epigenetic influences in key target genes involved in VILI responses; and v) novel therapeutic strategies for VILI. The key novel genes that comprise the focus of each Project were identified by our genomic–intensive approaches and selected for their capacity to contribute to a spectrum of VILI responses from VILI-induced lung inflammation, increased vascular permeability and injury (Projects #1 and #2); to VILI resolution with restoration of lung vascular barrier integrity (Project #3). These strategies are integrated across our three PPG projects and represent the thematic underpinnings of this PPG. Studies will be conducted by an outstanding group of gifted and interactive translational scientists. Project #1 will examine the NF-κB- dependent mechanisms (including protein nitration) by which VILI downregulates expression of SOX18, a critical lung vascular barrier-protective transcription factor (TF), and the key tight junction protein, claudin 5. The influence of the mechanosensitive receptor, TRPV4 on mitochondrial ROS and mechanical stress-associated TFs such as HIF2α will be explored. Project #2 will extend novel insights regarding the critical role of secreted extracellular NAMPT (eNAMPT), a nicotinamide phosphoribosyltransferase, in VILI and ARDS. Excessive mechanical stress induces NAMPT expression and eNAMPT ligates TLR4 (Toll-like receptor 4) to induce NF-κB signaling and inflammatory lung injury. Project #2 will interrogate novel mechanisms of NAMPT secretion, the influence of NAMPT/TLR4 SNPs, and NAMPT and TLR4 as therapeutic targets. Project #3 will interrogate genetic and epigenetic regulation of mechanical stress-mediated sphingosine 1-phosphate receptor expression (S1PR1, S1PR3) and the role of VILI-induced nitration of Rac1 and RhoA GTPases in lung vascular barrier regulation. The synergy derived from the interaction between individual Projects, as well as with our scientific Cores, with enviable expertise in molecular biology (B), genetic epidemiology (B), pre-clinical models of disease (C), and protein chemistry & Biophyics (D), will advance our programmatic approaches and promote the development of novel, individualized therapies to attenuate VILI especially in populations at risk for ARDS.

节目概要 机械通气是抢救急性呼吸衰竭危重患者生命的干预措施 呼吸窘迫综合征（ARDS），也会产生过度的机械应力，加重肺损伤， 呼吸机诱导的肺损伤（VILI）。VILI和ARDS的病理生物学有许多共同点， 炎症特征，包括由于内皮细胞（EC）损失导致的肺血管通透性增加 屏障完整性对VILI病理生物学的见解是渐进的，没有实现可行的治疗方法。该PPG 强烈的重点是增加我们的理解：i）转录因子，中继的影响， 过度的机械应力; ii）导致EC损伤的分子信号传导途径，包括 机械敏感性钙离子调节受体，瞬时受体电位阳离子通道亚家族V成员4 iii）影响VILI中涉及的关键信号传导途径的翻译后修饰（PTM）; iv）参与VILI应答的关键靶基因中的遗传和表观遗传影响;和v）新的 VILI的治疗策略通过以下方法确定了构成每个项目重点的关键新基因： 我们的基因组密集型方法，并选择他们的能力，以促进频谱VILI VILI诱导的肺部炎症、血管通透性增加和损伤的反应（项目#1和#2）; VILI消退，肺血管屏障完整性恢复（项目#3）。这些战略是一体化的 在我们的三个PPG项目中，代表了这个PPG的主题基础。研究将 由一群杰出的天才和互动的翻译科学家进行。项目1将检查NF-κB- VILI通过依赖性机制（包括蛋白质硝化）下调SOX 18的表达， 关键的肺血管屏障保护性转录因子（TF）和关键的紧密连接蛋白claudin 5。的 机械敏感性受体TRPV 4对线粒体ROS和机械应力相关的影响 将探索TF如HIF 2 α。项目#2将扩展关于分泌的关键作用的新见解， 细胞外NAMPT（eNAMPT），烟酰胺磷酸核糖转移酶，在VILI和ARDS。过度 机械应力诱导NAMPT表达，eNAMPT连接TLR 4（Toll样受体4）诱导NF-κB 信号传导和炎性肺损伤。项目#2将询问NAMPT分泌的新机制， NAMPT/TLR 4 SNP的影响，以及NAMPT和TLR 4作为治疗靶点。项目#3将询问 机械应力介导的1-磷酸鞘氨醇受体表达的遗传和表观遗传调控 （S1 PR 1，S1 PR 3）及VILI诱导Rac 1和RhoA GTP酶硝化在肺血管屏障中的作用 调控协同作用来自于各个项目之间的相互作用，以及与我们的科学 核心，在分子生物学（B），遗传流行病学（B）， 疾病（C）和蛋白质化学与生物物理学（D），将推进我们的计划方法，并促进 开发新的、个体化的疗法来减轻VILI，尤其是在有ARDS风险的人群中。