Tuesday, April 30, 2024
4/30/2024
Project Summary Many studies have highlighted a large incidence of hemostatic derangements in the form of hypercoagulable and hypofibrinolytic states following SARS-CoV-2 infection. These hemostatic disturbances are fueled by and a consequence of the concomitant activation of the endothelium following a severe inflammatory response, with likely contribution from many other pathways and components, such as the complement pathway and neutrophil activation. In COVID-19 patients, the resulting hyperinflammation, vascular dysfunction, and systemic hypercoagulability, collectively referred to as COVID-19-associated coagulopathy (CAC), manifests as the increased tendency of micro-thrombosis of different organs leading to organ dysfunction, venous thromboembolism, pulmonary embolism, and deep vein thrombosis. Reducing the deleterious impact of CAC during severe SARS-CoV-2 infections continues to represent a major therapeutic challenge. Despite the enormous effort exerted during the pandemic to understand the pathological mechanisms responsible for the severity of SARS-CoV-2 infections, a major knowledge gap about the drivers and mechanisms underlying CAC still exists. Furthermore, as the link between CAC and long COVID becomes more apparent, understanding CAC is more urgent than ever. Proposed studies are designed to gain knowledge on the drivers and mechanisms underlying CAC and will test the feasibility of several potential pharmacological approaches to blunt it. Levering our novel and carefully optimized mouse model of COVID-19 and CAC, relying on a human pathological SARS- CoV-2 strain and recapitulating major pathological alterations and development of CAC observed in human patients presents a unique opportunity for hypotheses-driven research in a controlled and systematic manner to gain important new insights on CAC. Mimicking worldwide observations that males are more susceptible to severe disease after SARS-CoV-2 infection compared to females, a sex-dependent bias in disease severity was also observed in our model that was accompanied by striking temporal, quantitative, and qualitative differences in the development of CAC. Aim 1 will characterize the major molecular determinants of the sex-biased disease severity and development of CAC in our mouse model of COVID-19 and CAC. Key questions that will be addressed are the extent to which the sex bias originates from hormonal differences, whether estrogens are protective and/or androgens are deleterious, and whether hormonal supplementation therapy can alter the development of CAC. These studies will help identify novel pathways and targets for CAC. Aim 2 will expand on our preliminary data to characterize von Willebrand Factor (VWF)’s function(s) and protein/protein interaction(s) that are responsible for modulating survival during SARS-CoV-2 infection and development of CAC. The results of these studies will increase our knowledge of the mechanisms involved in regulating the finely tuned interaction between the immune, endothelial, and coagulation systems upon SARS-CoV-2 infection, possibly leading to the identification of new therapeutical targets for the treatment of CAC.
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