Targeting divergent roles of caspase 3 to promote endothelial barrier recovery

Active Project Grant Awarded Last action

Award ID
R01HL173981
Recipient
Awarding agency
Obligated
$5,125,328

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 64% complete
Place of performance
Baltimore, MD 21205, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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 MK2 facilitates transport of caspase 3 into the nucleus in vitro. 2) determine the mechanism(s) of active cytoplasmic caspase 3 in promoting endothelial cell proliferation in vitro. 3) elucidate the role of cytoplasmic endothelial caspase 3 in accelerating recovery following lung injury.

Transactions

Action Obligated Date
Amendment $733,696
Amendment $0
Amendment $0
Amendment $75,112
Amendment $75,112
Amendment $676,013
Amendment $676,013
Amendment $676,013
Amendment $46,552
Amendment $46,552
Amendment $706,755
Amendment $706,755
Original award $706,755
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Subawards

Subrecipient Amount Awarded
University Of Louisville Targeting Divergent Roles of Caspase 3 to Promote Endothelial Barrier Recovery $105,639

Quick answers

Who received award R01HL173981?

R01HL173981 was awarded to The Johns Hopkins University by National Heart Lung and Blood Institute (National Institutes of Health) on April 1, 2024.

How much is award R01HL173981 worth?

$5,125,328 has been obligated on R01HL173981.

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