Targeting determinants of sars-COV-2 host interaction in airways

This $131,988 Project Grant from the National Heart, Lung and Blood Institute, part of the Department of Health and Human Services, supports research targeting determinants of SARS-CoV-2 host interaction in airways. Funded through the Cardiovascular Diseases Research program, the grant aims to identify master regulator proteins that mechanistically regulate SARS-CoV-2 interactions in the airways. Using organotypic airway epithelial culture and systems biology tools at Columbia University, the grantee will investigate how SARS-CoV-2 infection influences the local milieu to alter epithelial architecture and cell-specific programs. The work seeks to reduce viral load and counteract deleterious viral effects by pharmacologically targeting the identified master regulators. Outcomes may lead to novel COVID-19 therapeutic approaches. Performance runs through October 2021 at Columbia University in New York City.

Abstract

The studies in this F32 project focus on how sars-COV-2 infection influences the local milieu to alter epithelial architecture and cell type-specific programs of the airway epithelium. The goal is to identify and target master regulator (MR) proteins that mechanistically regulate sars-COV-2 interactions in the airways. The ongoing coronavirus disease 2019 (covid-19) pandemic has been a major public health concern for its unprecedented high mortality and morbidity. Accumulated evidence shows that the upper airway epithelium serves as the front-line target for viral entry and a reservoir for early viral replication, suggesting a key role for the airway epithelial cells in viral transmission. The massively higher transmission rate of the sars-COV-2 compared to other coronaviruses has been suggested to be a function of the major alterations in the host's transcriptional programs controlling airway epithelial cell behavior and barrier function fostering viral replication. The central hypothesis of this proposal is that identifying and pharmacologically targeting master regulators of the epithelial response to sars- COV-2 in the airways will reduce the viral load and counteract or prevent the deleterious viral effects in the respiratory tract. Here i propose to use an established organotypic airway epithelial culture system and systems biology analytical tools in combination with a high-throughput platform for drug screening available at columbia to investigate these issues. The identification of these regulators can lead to the development of novel therapeutic approaches to covid-19.