# Restoration of Lung Vascular Barrier Integrity

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $2,265,727

## Abstract

Overall Abstract of the Program
Endothelial barrier dysfunction is a central factor in the pathogenesis of protein-rich lung edema formation
and lung inflammation, the hallmarks of acute respiratory distress syndrome (ARDS). Due to the complexity
of these conditions, attempts to develop drugs and cell-based therapies have thus far not been successful.
Thus, whereas previously explored therapeutics specifically targeted the complex multistep process that
occurs during the lung injury phase, here we propose to focus on processes underlying the resolution of
vascular leakage and pulmonary edema. The central hypothesis of the Program Project application for
years 16 to 20 is that resealing of the endothelial barrier at the level of adherens junctions (AJs) is required to
restore junctional integrity, and thereby to normalize lung fluid balance. The research focus in all Projects will
thus be on delineating the role of overlapping but specialized signaling pathways that operate to re-seal AJs,
and on this basis, identifying novel therapeutic targets that can be harnessed to reverse the course of the
disease. In Project 1, Dr. Asrar Malik, PI, will test the novel hypothesis that restoration of lung endothelial
barrier is regulated by two complementary mechanisms, the vascular endothelial protein tyrosine
phosphatase (VE-PTP)-mediated stabilization of VE-cadherin, and the Rac1-mediated formation of adhesive
bonds between VE-cadherin molecules at AJs. These studies will define the signaling mechanisms activated
by VE-PTP interaction with VE-cadherin, and with tyrosine kinase receptor Tie2 in regulating the integrity of
the lung endothelial barrier. In Project 2, Dr. Jalees Rehman, PI, will test the central hypothesis that
inflammation-induced glycolysis in lung endothelial cells (ECs) is an intrinsic mechanism necessary for
restoration of endothelial barrier function. Studies will examine the roles of the key rate-limiting kinase in
regulating glycolysis 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFK-FB3), and activation of
glutamine metabolism in mitochondria in endothelial barrier repair. In Project 3, Dr. Dolly Mehta, PI, will test
the fundamental hypothesis that S1P receptor-1 (S1PR1) expression regulates lung vascular barrier integrity,
and is essential for restoring lung fluid balance. These studies will define mechanisms controlling the cell
surface expression of S1PR1 in ECs following lung injury, and the role of interaction of S1PR1 with the VEGF
receptor (VEGFR2) in establishing vascular endothelial integrity. In Project 4, Dr. Viswanathan Natarajan, PI,
will test the hypothesis that spatial and coordinated production of lipid second messengers such as
phosphatidic acid by phospholipase D2 (PLD2) and of S1P by sphingosine kinase 1 (SphK1) is required for
lamellipodia formation and recycling of VE-cadherin to AJs to restore the EC barrier. These studies will define
the function of these bioactive lipids as key mediators inducing the f...

## Key facts

- **NIH application ID:** 9970518
- **Project number:** 5P01HL060678-20
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Asrar B. Malik
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,265,727
- **Award type:** 5
- **Project period:** 2000-03-08 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970518

## Citation

> US National Institutes of Health, RePORTER application 9970518, Restoration of Lung Vascular Barrier Integrity (5P01HL060678-20). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970518. Licensed CC0.

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