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.

程序摘要 机械通气，对急性呼吸衰竭患者的救生干预 呼吸窘迫综合征（ARDS）也会产生过多的机械应力，以增加肺损伤，A 综合征称为通风诱导的肺损伤（VILI）。 Vili和Ards的病理生物学共享许多 炎症特征，包括由于内皮细胞损失而导致肺血管通透性的增加（EC） 障碍完整性。对VILI病理生物学的见解是渐进的，没有实现可行的疗法。这个ppg 强烈关注我们对以下理解：i）转录的转录因素 过度的机械应力； ii）导致EC损伤的分子信号通路，包括初始激活 机械敏感的Ca2+调节受体，瞬态受体电势阳离子通道亚家族V成员4 （TRPV4）; iii）翻译后修改（PTM），影响VILI涉及的关键信号通路 回应； iv）与VILI反应有关的关键靶基因的遗传和表观遗传影响；和v）小说 Vili的治疗策略。构成每个项目重点的关键新颖基因由 我们的基因组密集型方法，并选择了其能力有助于Vili的能力 Vili引起的肺注射，血管渗透性增加和损伤的反应（项目＃1和＃2）；到 VILI分辨率恢复了肺血管屏障完整性（项目＃3）。这些策略是整合的 在我们的三个PPG项目中，代表了该PPG的主题基础。研究将是 由一群杰出的有天赋和互动的翻译科学家进行。项目＃1将检查NF-κB- 依赖机制（包括蛋白硝化），通过该机制下调Sox18的表达，A 关键的肺血管屏障保护因子（TF）和关键的紧密连接蛋白，Claudin 5。 机械受体TRPV4对线粒体ROS和机械应力相关的影响 将探索诸如HIF2α之类的TF。项目＃2将扩展有关分泌的关键作用的新颖见解 细胞外NAMPT（ENAMPT），一种烟酰胺磷酸贝糖基转移酶，中的VILI和ARDS。过多的 机械应力诱导NAMPT的表达，并陶器连接TLR4（Toll-like受体4）诱导NF-κB 信号传导和炎症性肺损伤。项目＃2将询问NAMPT分泌的新型机制， NAMPT/TLR4 SNP，NAMPT和TLR4作为治疗靶标的影响。项目＃3将审问 机械应力介导的1-磷酸受体表达的遗传和表观遗传调节 （S1PR1，S1PR3）以及VILI诱导的Rac1和RhoA GTPases在肺血管屏障中的作用 规定。来自单个项目之间的相互作用以及我们的科学的协同作用 核心，具有令人羡慕的分子生物学专业知识（B），遗传流行病学（B），前临床模型 疾病（C）和蛋白质化学与生物（D）将推进我们的程序化方法并促进 开发新型的个性化疗法以减轻Vili，尤其是在有ARDS风险的人群中。