# Mechanism of BET Proteins in Th17 Cell Differentiation

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $342,914

## Abstract

PROJECT SUMMARY
This administrative supplement application is submitted for the parent award (5R01AI124465) in
response to NIAID’s Notice of Special Interest (NOT-AI-20-031) “Severe Acute Respiratory Syndrome
Coronavirus (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19)”, as well as “Administrative
Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp - Clinical Trial
Optional)” (PA-18-591). The outbreak of the new coronavirus (SARS-CoV-2) infection is spreading to
every continent around the world at an astonishing speed. As of April 15, 2020, coronavirus disease
2019 (COVID-19) has been confirmed in 2,035,764 people worldwide, causing a mortality of 6.42%,
exceeding far beyond a mortality rate of <1% from influenza. Effective treatment is urgently needed to
stop the rapid spread of SARS-CoV-2 infection in this devastating pandemic. While current focus is on
developing novel therapeutics including antivirals and vaccines, mounting evidence show that many
severe COVID-19 patients suffer from respiratory failure by acute respiratory distress syndrome
(ARDS), the leading cause of COVID-19 mortality. In this study, we aim to address this major
unmet medical need. Clinically, host cells elicit two-phased responses to SARS-CoV-2 infection. In
an early incubation and non-severe stage, immune cells such as macrophages detect the virus and
produce cytokines to eliminate the virus. But, when a protective immune response is impaired, the
virus propagates, and the disease is transitioned to a severe stage where innate inflammation is
induced by virus-caused massive tissue damage with uncontrolled cytokine release (aka Cytokine
Storm) from inflammatory macrophages and granulocytes, resulting in ARDS in the lungs. Ascended
pro-inflammatory cytokines such as IL-6, IL-10, IL-17, GM-CSF, MCP-1, IFN-γ, and TNF-α are
reported in severe COVID-19 patients. Lung hyper-inflammation is the main cause of life-threatening
respiratory disorders at the severe stage. Notably, our study shows that transcriptional activation of
these inflammatory cytokines is directed by major transcription factors NF-kB and STAT3 in concert
with chromatin regulators BRD2 and BRD4, and that their activities can be effectively blocked by
chemical inhibitors. Motivated by our findings, in this study, we propose to identify and repurpose
FDA-approved drugs to suppress SARS-CoV-2-induced cytokine storm through simultaneously
blocking NF-kB and STAT3 signaling pathways. We will achieve this goal by addressing the two
specific aims: (1) identify FDA-approved drugs to block uncontrolled cytokine release induced by
SARS2-CoV-2; (2) validate chemical inhibition of hyperinflammation in human immune cell lines
including human peripheral blood mononuclear cells from COVID-19 patients.

## Key facts

- **NIH application ID:** 10146806
- **Project number:** 3R01AI124465-05S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ming-Ming Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,914
- **Award type:** 3
- **Project period:** 2020-05-22 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146806

## Citation

> US National Institutes of Health, RePORTER application 10146806, Mechanism of BET Proteins in Th17 Cell Differentiation (3R01AI124465-05S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10146806. Licensed CC0.

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