Mechanical ventilation, a life-saving intervention in critically ill patients with respiratory failure due to acute res- piratory 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 in- flammatory features including increases in lung vascular permeability due to loss of endothelial cell (EC) barri- er 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 exces- sive 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 re- sponses; 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 respons- es 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 conduct- ed by an outstanding group of gifted and interactive translational scientists. Project #1 will examine the NF-?B- dependent mechanisms (including protein nitration) by which VILI downregulates expression of SOX18, a criti- cal 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 HIF2? 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 me- chanical stress induces NAMPT expression and eNAMPT ligates TLR4 (Toll-like receptor 4) to induce NF-?B 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 ge- netic 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 dis- ease (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.

Public Health Relevance

This PPG application is focused on the critical role of mechanical ventilation, a life-saving intervention in criti- cally ill patients with respiratory failure, in creating excessive mechanical stress that directly augments lung in- jury, a syndrome known as ventilator-induced lung injury (VILI). This PPG intensely focuses on understanding: i) the transcription factors that relay the effects of excessive mechanical stress; ii) PTMs that influence key sig- naling pathways involved in VILI responses; iii) genetic and epigenetic influences in key target genes involved in VILI responses; and iv) novel therapeutic strategies for VILI. Elucidating the contributions of genetics, epige- netics and PTMs to VILI pathobiology, will enhance therapeutic targeting and increase our knowledge of the genetic basis for ARDS health disparities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL134610-01A1
Application #
9417437
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Reineck, Lora A
Project Start
2018-02-05
Project End
2023-01-31
Budget Start
2018-02-05
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Arizona
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721