# Mechanism of BET Proteins in Th17 Cell Differentiation

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $419,789

## Abstract

PROJECT SUMMARY
This administrative supplement application is submitted for the parent award (5R01AI124465-
05) in response to NIH funding opportunity (NOT-AG-20-008), entitled “Alzheimer’s-focused
administrative supplements for NIH grants that are not focused on Alzheimer’s disease.”
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder of aging, affecting
about 44 million people worldwide with 5.5 million in the U.S. Amyloid plaques in the brain are
one of the pathological hallmarks of AD. The plaques mainly consist of fibrillary forms of amyloid
β peptide-40 (Aβ-40) and amyloid β peptide-42 (Aβ-42) produced from amyloid precursor
proteins by sequential cleavage. Despite the major drug development efforts targeting amyloid β
peptide cleavage and processing, nearly all experimental drugs tested for AD thus far have
failed to show significant efficacy. Recent studies show that Aβ peptides form aggregates that
induce oxidative stress and initiate the inflammatory process, leading to activation of microglial
and neurodegeneration in the brain, which is fueled by proinflammatory cytokines secreted by
CD4+ T-helper 17 (Th17) cells. These studies suggest a new therapeutic strategy of targeting
neuroinflammatory Th17 cells in the AD pathogenesis to prevent and treat AD. Studies from us
and others show that Th17 cell differentiation from naïve CD4+ T cells is tightly regulated in gene
transcription by coordinated activities of major transcription and chromatin regulators including
BET family protein BRD4. We recently developed a set of novel small-molecule compounds that
selectively target BRD4 activity for transcriptional expression of Th17 signature cytokines
including IL-17, IL-21, IL-22, and IL-23, and blocks over-development of Th17 cells in mice that
mimic the conditions of neuroinflammatory disorders in humans. Motivated by our favorable
findings, in this study, we propose to: (1) develop our CNS penetrant Th17 immunomodulators,
and (2) characterize them in the AD mouse model as a new immunomodulation treatment for
AD, which represents a major unmet medical need.

## Key facts

- **NIH application ID:** 10121773
- **Project number:** 3R01AI124465-05S2
- **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:** $419,789
- **Award type:** 3
- **Project period:** 2016-03-10 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121773

## Citation

> US National Institutes of Health, RePORTER application 10121773, Mechanism of BET Proteins in Th17 Cell Differentiation (3R01AI124465-05S2). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10121773. Licensed CC0.

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