# Targeting Divergent Roles of Caspase 3 to Promote Endothelial Barrier Integrity

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $403,295

## Abstract

Acute Respiratory Distress Syndrome (ARDS) is a devastating illness with an annual incidence
of 200,000 and a mortality of 40%. Sepsis is a major cause of ARDS, contributing up to ~80% of
ARDS cases. Endothelial barrier dysfunction is critical for the pathogenesis of vascular
permeability and the resulting tissue edema and profound hypoxia seen in ARDS. Endothelial
barrier dysfunction in sepsis is a complex phenomenon involving cytoskeletal changes in
response to pro-inflammatory mediators, where the actin cytoskeleton plays a pivotal role in
mediating endothelial barrier function and permeability. Interestingly, the same stimuli that lead
to cytoskeletal changes within the endothelium, e.g. activation of toll-like receptor 4, fas-ligand
and stress activated kinases, can also precipitate endothelial cell apoptosis. While cytoskeletal
changes are reversible and are eventually followed by recovery of the endothelial barrier,
endothelial cell apoptosis represents a final cellular fate and may be an irreversible determinant
of endothelial barrier disruption. In fact, after apoptotic-endothelial injury, restoration of barrier
function requires endothelial cell proliferation, migration and/or endothelial progenitor cell seeding
implying an irreversibility to apoptotic endothelial barrier disruption. These two mechanisms of
vascular permeability, bring about the possibility of a transition point linking reversal (cytoskeletal)
and irreversible (apoptotic) modes of endothelial barrier disruption that if identified, could be
exploited for therapeutic intervention. Many models used for understanding the pathophysiology
of endothelial barrier dysfunction have focused on the initiation phase of endothelial barrier
disruption. Recently new insights have started to emerge regarding the resolution of ARDS.
Understanding of both phases of ARDS has significant merit towards the development of
therapeutic targets. Importantly, molecular targets that integrate and lie at the intersection of these
two phases of ARDS could not only attenuate injury but concomitantly accelerate recovery. This
proposal will provide new insight into concurrent attenuation of endothelial barrier disruption and
promotion of endothelial barrier recovery by elucidating the molecular mechanisms by which
caspase 3 influences cytoskeletal de-remodeling and apoptotic-endothelial injury.

## Key facts

- **NIH application ID:** 9960561
- **Project number:** 5R01HL133413-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mahendra Damarla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,295
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960561

## Citation

> US National Institutes of Health, RePORTER application 9960561, Targeting Divergent Roles of Caspase 3 to Promote Endothelial Barrier Integrity (5R01HL133413-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9960561. Licensed CC0.

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