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CPNE5 in Cardiovascular Barrier Dysfunction and Septic Cardiomyopathy

Award Number: R01HL187149
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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CPNE5 in Cardiovascular Barrier Dysfunction and Septic Cardiomyopathy - Sepsis is characterized as life-threatening organ failure caused by an uncontrolled infection. Among organs affected, heart failure is recognized to be a major contributor to septic death. While it is well accepted that hyper- inflammation is a key culprit for sepsis-induced cardiomyopathy, therapeutic interventions aimed to dampen the inflammatory response in sepsis have failed to improve the survival outcome. Indeed, it has become evident that loss of vascular barrier integrity and increased endothelial permeability are fundamental pathological events that occur early in sepsis pertaining to organ failure and death. At present, dozens of molecules/factors related to vascular leakage have been identified. However, none of these has shown successfully in clinical trials to reduce septic mortality due to the complex and heterogeneous nature of the host response. Hence, continuing search for new factors that target to reduce vascular leakage is greatly needed. We recently discovered that plasma levels of Copine 5 (CPNE5), a poorly characterized member of the Copine family, were remarkably lower in human patients with sepsis than healthy donors,which were negativelycorrelatedwith vascular leakage biomarkers. Using a global CPNE5-knockout (KO) mouse model, we observed that loss of CPNE5 significantly augmented sepsis- induced vascular leakage, leading to greater cardiac dysfunction and higher mortality, compared to wild-type (WT) control mice. By contrast, in vitro overexpression of CPNE5 in endothelial cells (ECs) showed greater resistance to inflammation-induced monolayer leakage, compared to control cells. An initial mechanistic analysis by RNA- sequencingand bioinformatics showedthat the Wnt5a/β-catenin classical pathway was greatly inhibited in CPNE5- overexpressing ECs. Accordingly, the nuclear translocation of β-catenin was disrupted in CPNE5-ECs upon inflammatory insults, leading to reduced expression of multiple MMPs and ADAMs, well-known proteases that degrade EC junctional proteins. Importantly, activation of the Wnt5a/β-catenin pathway in ECs by both rWnt5a and LiCl offsets the CPNE5-induced reduction of monolayer leakage upon inflammatory challenge. Based on these pilot data, we hypothesize that CPNE5 is essential for protecting against sepsis-induced cardiovascular leakage via inhibition of the Wnt5a/β-catenin pathway. This hypothesis will be tested by pursuing three specific aims: 1) Define the precise role of CPNE5 in maintaining vascular integrity and cardiac function during sepsis, using a global KO and an EC-specific CPNE5-transgenic mouse models; 2) Identify the mechanism by which CPNE5-elicited protection against sepsis-induced vascular leakage and heart failure is associated with disruption of the Wnt5a/β- catenin signaling, using pharmaceutical agonists and antagonists; and 3) Evaluate the therapeutic potential of recombinant CPNE5 protein in treating sepsis. The proposed studies are expected to identify CPNE5 as a new protector against sepsis-induced vascular leakage and cardiomyopathy; a novel regulator of the Wnt5a-mediated classical signaling in ECs and if completed, the findings from this proposal would provide new therapeutic options for reducing cardiovascular dysfunction during sepsis, with the hope of improving survival outcomes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $753,539 )
2026	2026	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	1	7/23/2026	NEW	$753,539
														Subtotal = $753,539

Grand Total All Awards = $753,539

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CPNE5 in Cardiovascular Barrier Dysfunction and Septic Cardiomyopathy

Award Number: R01HL187149

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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