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Long Noncoding RNA Regulation in Complement-Mediated Endothelial Barrier Disruption: From Mechanism to Therapy

Award Number: R01HL178801
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: 04/30/2031

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Long Noncoding RNA Regulation in Complement-Mediated Endothelial Barrier Disruption: From Mechanism to Therapy - PROJECT SUMMARY/ABSTRACT Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are still life-threatening diseases in critically ill patients. Despite diagnosis and therapy for ARDS having been developed steadily over the last 50 years, its mortality has remained static at 30%-to-40% in the last decade. To date, there is no specific pharmacological interventions have been shown to improve outcomes. Thus, there is an urgent need to reduce the morbidity and mortality associated with ARDS, alleviate the burden on patients and their families, and save lives by improving lung health. In ALI/ARDS, endothelial cell death is a critical pathological event. Damage to pulmonary capillary endothelial cells compromises the integrity of the alveolar-capillary barrier, resulting in increased vascular permeability, pulmonary edema, and impaired gas exchange. Given the central role of endothelial injury in the pathogenesis of ALI/ARDS, therapeutic strategies that preserve endothelial cell viability and restore barrier function hold significant promise. Targeting mechanisms of endothelial cell death may offer a novel and effective approach to improve outcomes in patients with ALI/ARDS. Long noncoding RNAs (lncRNAs) have emerged as key regulators of gene expression, influencing a wide range of physiological and pathological processes. Increasing evidence suggests that lncRNAs play critical roles in the pathogenesis of ALI and represent promising targets for diagnosis and therapy. In our study, we identified an lncRNA, Lncenc1, that is markedly upregulated in murine lungs following bacterial infection. Notably, Lncenc1 deficiency conferred protection against Klebsiella pneumoniae (K. pneu)-induced lung injury and pulmonary edema. Mechanistically, we observed a significant increase in CD59 expression in lung tissues of Lncenc1- deficient mice compared to wild-type controls. CD59 is predominantly expressed on vascular endothelial cells and acts as a “suicide inhibitor” by blocking complement activation and membrane attack complex (MAC) formation on the cell surface. Loss of Cd59 exacerbated K. pneu-induced ALI, resulting in increased pulmonary vascular leakage and mortality. Our central hypothesis is that Lncenc1 regulates endothelial cell death by modulating CD59-dependent complement activation and MAC formation during bacteria-induced ALI. We propose that the Lncenc1–CD59– MAC axis constitutes a novel regulatory pathway and therapeutic target that governs complement-mediated endothelial injury in ALI. Building on this mechanistic insight, we will test whether targeting Lncenc1 and CD59 can restore endothelial barrier integrity and improve clinical outcomes in murine models of ALI.


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 = $588,284 )
2026	2026	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Lung Diseases Research	000	1	8/3/2026	NEW	$588,284
														Subtotal = $588,284

Grand Total All Awards = $588,284

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Long Noncoding RNA Regulation in Complement-Mediated Endothelial Barrier Disruption: From Mechanism to Therapy

Award Number: R01HL178801

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: 04/30/2031

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