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

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $753,307

## Abstract

PROJECT SUMMARY
Acute Respiratory Distress Syndrome (ARDS) is a devastating illness with an annual incidence of 200,000 and
a mortality of 40%. 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 ARDS is a
complex phenomenon involving cytoskeletal changes in response to pro-inflammatory mediators, which can also
precipitate endothelial cell apoptosis, a programmed form of cell death. While cytoskeletal changes are reversible
and are eventually followed by recovery of the endothelial barrier, endothelial cell apoptosis represents a final
cellular fate and 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.
Therefore, a transition point likely exists between pro-apoptotic signaling (injury phase) and pro-proliferative
signaling (recovery phase) leading to endothelial barrier restoration; further insight into which would identify
therapeutic targets that not only reduce severity of ARDS but also facilitate recovery.
Our laboratory has identified non-canonical functions for caspase 3, a terminal enzyme of the apoptotic cascade.
Traditionally, activation of caspase 3 had been considered as the point of no return in the execution of apoptosis.
We identified a disconnect between activation of caspase 3 and the execution of apoptosis. In initial work, we
found loss of the signaling molecule mitogen activated protein kinase activated protein kinase 2 (MK2), resulted
in prevention of both apoptosis and endothelial barrier dysfunction despite activation of caspase 3. Interestingly,
in these experiments active caspase 3 was sequestered in the cytoplasm. We have also shown caspase 3
enhances barrier integrity is via cytoskeletal changes that increase centrifugal forces, reminiscent of changes
required for cellular migration. We have exciting preliminary data showing caspase 3 promotes migration and
proliferation. Further, our preliminary data suggests caspase 3 functions via yes activated protein (YAP), a known
regulator of migration and proliferation implicated in angiogenesis and lung development. However, there is little
known about the role of YAP in endothelial barrier recovery following lung injury and the molecular regulators
that initiate YAP signaling in this process. Based on our previous findings and preliminary data, we hypothesize
the association between caspase 3 and MK2 is necessary for nuclear translocation of caspase 3 and the
apoptosis-promoting function of caspase 3. We further hypothesize that inhibiting the association between active
caspase 3 and MK2 converts caspase 3 to a pro-proliferative factor, via YAP signaling, thereby accelerating
endothelial barrier recovery. Thus, the Aims of this study are: 1) determine the mechanisms by which...

## Key facts

- **NIH application ID:** 10901121
- **Project number:** 1R01HL173981-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mahendra Damarla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $753,307
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901121

## Citation

> US National Institutes of Health, RePORTER application 10901121, Targeting Divergent Roles of Caspase 3 to Promote Endothelial Barrier Recovery (1R01HL173981-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10901121. Licensed CC0.

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