Saturday, May 4, 2024
5/4/2024
SUMMARY Endothelial cell (EC) dysfunction is a key factor that promotes poor host defense, pro-thrombotic cardiovascular complications and bleeding during respiratory viral infections. The applicant’s laboratory has made long-standing contributions in vascular effects of sphingosine 1-phosphate (S1P), a circulating lipid mediator important for EC resilience. This protective pathway is preferentially activated by HDL-bound S1P, thus counteracting EC dysfunction and pathophysiology. However, the role of S1P in influenza viral infections in the context of thrombosis and bleeding complications is poorly understood. This proposal develops a novel paradigm to enhance vascular resilience while minimizing thrombotic and bleeding complications during virus-induced pulmonary injury. We have developed designer HDL-like nanoparticles that chaperone S1P, namely, ApoA1- ApoM (A1M)/S1P, for therapeutic activation of EC S1PR1 and suppression of vascular leak. A1M/S1P either alone or together with other barrier protective agents such as angiopoietin-1 (ANGPT-1) and prostacyclin (PGI2) enhanced EC barrier function in endothelial cells. In addition, the ApoA1 moiety of A1M suppressed cytokine- induced NFkB activation and inflammatory gene expression. We hypothesize that sustained activation of S1PR1/Gi signaling by HDL-S1P and cooperative interactions between EC protective pathways (ANGPT1/ Tie2 and PGI2/IP receptor) enhances pulmonary vascular recovery from respiratory viral infections without inducing prothrombotic transformation of the endothelium. Specific aim 1 will evaluate HDL-S1P activation of protective endothelial S1PR1/Gi signaling. Genetic mouse models of S1PR1 loss of function (EC knockout), gain of function (EC transgenic) and Gi-biased signaling (S5A phosphorylation-defective mutant), Apom KO or Apom TG mice will be analyzed to determine alveolar microvascular leak, integrity, thrombosis, bleeding and resolution of inflammation during influenza virus-induced pneumonitis. Single cell (sc)RNA-seq data from mice with viral pneumonitis will be deconvoluted to determine molecular mechanisms of paracrine signal networks between EC and pericytes important in microvascular resilience. The second aim will determine the mechanisms by which albumin-S1P/S1PR1 signaling in EC promotes thrombosis in the context of viral infection. We will use Tie2 agonists together with EC-targeted S1PR1 agonists to control bleeding in the setting of influenza infection. The third aim will develop combinatorial therapeutic approaches containing novel HDL-like nanoparticles and Tie2 activators to suppress EC injury and thromboinflammation during viral host defense responses. Designer HDL particles containing S1P that enhances the vascular resilience and HDL particles that carry stable prostacyclin (PGI2) analogs will be combined with Tie2 activators to suppress thrombosis and bleeding in lung on chip and mouse models. Together, this proposal aims to achieve a mechanistic understanding of EC pathophysiology during respiratory viral infections and develop novel therapeutic strategies.
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