Ryan Kwok, PhD
Postdoctoral Trainee
Department of Pharmacology & Regenerative Medicine
Advisor: Yulia Komarova Heading link
Title: Inhibitor of End Binding protein 3 promotes resolution of acute lung injury
Abstract: Acute respiratory distress syndrome (ARDS) is the acute onset of non-cardiogenic pulmonary edema, hypoxemia, and respiratory failure, conditions associated with a high mortality rate. ARDS is frequently caused by lung infections including SARS-CoV-2. In light of the COVID-19 pandemic, development of therapeutic approaches to combat ARDS have become an urgent unmet medical need. As increased vascular leakage is a culprit of alveolar damage and lung inflammation, we hypothesize that an effective therapy against vascular leakage should improve the clinical outcome of ARDS patients. We have identified a drug candidate Vascular Therapeutics (VT)-109, an allosteric inhibitor of End Binding protein 3 (EB3), which contributes to vascular leakage by amplifying pathological calcium signaling in endothelial cells. In our early study, VT-109 was proven to reduce mortality and vascular leakage in endotoxin and polymicrobial sepsis models of ARDS. Now, we are testing VT-109 in the models of SARS-CoV-2-induced ARDS using transgenic mice expressing human ACE2. We also aim to understand the mechanism of VT-109 action. Transcriptome analysis of lung endothelial cells in mice challenged with endotoxin showed that VT-109 upregulated several FOXM1 target genes, suggesting that it promotes endothelial cell regeneration by activating the FOXM1 pathway. We intend to investigate the pharmaceutical effects of VT109 in activating FOXM1 pathway.