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.

计划概要 机械通气是对急性呼吸衰竭危重患者的一种挽救生命的干预措施 呼吸窘迫综合征 (ARDS) 也会产生过度的机械应力，从而加重肺损伤， 称为呼吸机诱发性肺损伤 (VILI) 的综合征 VILI 和 ARDS 的病理学有许多共同点。 炎症特征，包括由于内皮细胞 (EC) 损失导致肺血管通透性增加 对 VILI 病理学的了解不断增加，但尚未实现可行的治疗方法。 重点关注增加我们对以下方面的理解：i) 传递以下效应的转录因子 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 Ca2+ 调节受体，瞬时受体电位阳离子通道亚家族 V 成员 4 (TRPV4)；iii) 影响 VILI 关键信号通路的翻译后修饰 (PTM) iv) 参与 VILI 反应的关键靶基因的遗传和表观遗传影响；以及 v) 新颖 VILI 的治疗策略是由以下人员确定的：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因其对一系列 VILI 做出贡献的能力而被选中 VILI 引起的肺部炎症、血管通透性增加和损伤的反应（项目#1 和#2）； VILI 的解决与恢复肺血管屏障完整性（项目#3）。 涵盖我们的三个 PPG 项目并代表本 PPG 研究的主题基础。 由一群才华横溢且互动的转化科学家进行的项目 #1 将检查 NF-κB-。 VILI 下调 SOX18 表达的依赖机制（包括蛋白质硝化） 关键的肺血管屏障保护转录因子 (TF) 和关键的紧密连接蛋白 Claudin 5。 机械敏感受体 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见解。 VILI 和 ARDS 中的细胞外 NAMPT (eNAMPT) 是一种烟酰胺磷酸核糖基转移酶。 机械应力诱导 NAMPT 表达，eNAMPT 连接 TLR4（Toll 样受体 4）诱导 NF-κB 项目 #2 将探究 NAMPT 分泌的新机制，即 NAMPT 分泌的新机制。 NAMPT/TLR4 SNP 的影响，以及 NAMPT 和 TLR4 作为治疗靶标，项目 #3 将进行研究。 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 (S1PR1、S1PR3) 以及 VILI 诱导的 Rac1 和 RhoA GTPases 硝化在肺血管屏障中的作用 监管的协同作用源自各个项目之间的相互作用以及我们的科学。 核心，在分子生物学 (B)、遗传流行病学 (B)、临床前模型方面拥有令人羡慕的专业知识 疾病（C）和蛋白质化学与生物物理学（D），将推进我们的程序化方法并促进 开发新的个体化疗法来减轻 VILI，特别是在有 ARDS 风险的人群中。