Roles for CLAUDIN11 in regulating endothelial barrier function

The National Heart, Lung, and Blood Institute awarded Emory University $198,728 on September 30, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the role of claudin11 in regulating endothelial barrier function in sepsis.

The research examines how the tight junction protein claudin11 forms a signaling hub with pannexin1 to regulate vascular barrier function in response to inflammatory cytokines associated with sepsis. Sepsis affects approximately 1.7 million Americans annually with an estimated financial burden of $62 billion in hospitalizations and nursing care. A key feature of sepsis is breakdown of endothelial cell barrier function—the primary barrier lining blood vessels that regulates exchange of fluid, waste, and nutrients between blood and tissue. The project tests the hypothesis that claudin11, expressed in a venous-specific manner, mediates endothelial barrier defects caused by TNF through a pannexin1-dependent pathway. Work is performed in Atlanta, Georgia, with a period of performance through September 29, 2029. This is a Project Grant, classified as assistance funding, with the Emory University Office of Sponsored Programs serving as the recipient organization.

Abstract

According to the CDC, approximately 1.7 million people in america develop sepsis, an uncontrolled bacterial infection, each year where the financial burden is estimated to be $62 billion annually in hospitalizations and nursing care. Sepsis is a global threat with no specific treatment options. A key feature of sepsis is the breakdown of endothelial cell barrier function. Endothelial cells line blood vessels and act as the primary barrier for exchange of fluid, waste, and nutrients between the blood and tissue. Baseline permeability of the endothelial barrier is vessel dependent, where permeability is low in arterioles and high in post-capillary venules. Endothelial barrier permeability is regulated through the apical junctional complex composed primarily of tight junctions and adherens junctions. Tight junction proteins, specifically claudins, directly regulate permeability of the endothelial barrier where CLAUDIN11 is expressed in a venous specific manner, making IT a focus of this study. Maintenance of vascular homeostasis is important in preventing the pathologic consequences of disease, including sepsis, which occurs from a dysregulated inflammatory response to infection. This dysregulated immune response induces changes in endothelial barrier function making the molecular mechanisms underlying endothelial barrier function crucial for development of novel therapeutics. Recent work has demonstrated that TNF, a contributing factor to inflammation in sepsis, causes a defect in venous endothelial barrier function that is mediated through a PANNEXIN1-dependent pathway. The central hypothesis of this proposal is that the tight junction protein CLDN11 forms a signaling hub with PANNEXIN1 that regulates barrier function in response to inflammation. I will test this hypothesis in two aims: aim 1 will investigate protein composition changes in response to pro- inflammatory cytokines using bioid; aim 2 will examine changes in vessel permeability in response to pro- inflammatory cytokines measured by changes in transendothelial resistance, immunoblot, and immunofluorescence. A long-term goal of this project is to identify potential therapeutic targets that promote endothelial cell barrier function that would otherwise be compromised as a result of inflammation and sepsis.