# Cytoskeletal Regulation of Lung Endothelial Pathobiology in ARDS > **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2022 · $2,139,356 ## Abstract ABSTRACT: The critical role of lung endothelial cells (ECs) and the ARDS vascular endotype in ARDS pathobiology is being dramatically highlighted in the current global COVID-19 pandemic. This highly translational PPG renewal will address the contribution of unchecked EC permeability to the devastating multi-organ failure and mortality of ARDS by providing a comprehensive understanding at the molecular and genomic level of vascular barrier reg- ulation and repair. This renewal maintains its focus on the critical role of the EC cytoskeleton in the pathobiology of ARDS and ventilator-induced lung injury (VILI) and seeks to directly address the unmet need for FDA- approved ARDS pharmacotherapies that attenuate lung vascular permeability and inflammation. We propose 4 highly clinically-relevant, tightly-woven PPG Projects centered on specific lung EC target proteins/genes that are involved in: i) the unchecked vascular permeability and injury in ARDS; ii) vascular responses to exces- sive mechanical stress in VILI; iii) contributing to the genetic basis for ARDS health disparities in African descent subjects; and, iv) providing novel ARDS therapeutic opportunities. Thematic integration across all projects includes functional characterization of ARDS-associated SNPs and CpG sites in PPG target genes and the role of ROS in transcriptional and biochemical regulation of peripheral cytoskeletal remodeling, formation of cytoskeletal-driven lamellipodia and focal adhesion (FA) reorganization that promotes EC gap closure. Project #1 will utilize system biology approaches to define novel cytoskeletal regulation of EC barrier responses by the multi-functional non-muscle myosin light chain kinase isoform (nmMLCK) and its cytoskeletal-binding partner, cortactin. Project #2 (a new PPG addition) extends our recent report that EC secretion of the damage-associated molecular pattern (DAMP) protein, eNAMPT (nicotinamide phosphoribosyltransferase), is critical to ARDS in- flammatory permeability and injury via eNAMPT ligation of the Toll-like receptor 4 (TLR4). Project #3 will inter- rogate the novel regulation by integrin β4 (ITGB4) and kindlin2, of the bidirectional signaling between the cyto- skeleton and focal adhesion (FA) dynamics which promotes lamellipodial-mediated closure of inflammation-in- duced EC gaps. Project #4 (a new PPG Project) will elucidate interactions between key barrier-regulatory re- ceptors: sphingosine-1-phosphate (S1P) receptor 1 (S1PR1), S1PR3, and P-selectin which regulate leukocyte recruitment and lung vascular leak via ligation by P-selectin glycoprotein ligand 1 (PSGL1). Supported by four highly interactive cores woven into each PPG Project (Administrative, Genome/Proteome, Preclinical Animal Model, Biophysical Imaging), this PPG will continue to leverage the outstanding scientific environments at the University of Arizona and University of Illinois, and the outstanding PPG translational team of interactive basic and physician-scientist... ## Key facts - **NIH application ID:** 10496455 - **Project number:** 2P01HL126609-06A1 - **Recipient organization:** UNIVERSITY OF ARIZONA - **Principal Investigator:** Joe G. N. Garcia - **Activity code:** P01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $2,139,356 - **Award type:** 2 - **Project period:** 2016-09-20 → 2023-01-05 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10496455 ## Citation > US National Institutes of Health, RePORTER application 10496455, Cytoskeletal Regulation of Lung Endothelial Pathobiology in ARDS (2P01HL126609-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10496455. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*