# "Investigating the Regulation of TNFα/IFNγ Synergy by Transcriptional Coativators in Endothelial Cells"

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2020 · $48,100

## Abstract

Project Summary
Atherosclerosis is the culmination of a chronic inflammatory response to endothelial cell injury. Central
to the initiation and progression of atherosclerotic plaques are cytokines, signaling molecules which
are secreted by and act on leukocytes, endothelial cells, and vascular smooth muscle cells. In
particular, human atherosclerotic plaques exhibit an increase in several members of the interleukin
family, TNFα, and IFNγ. TNFα and IFNγ have been shown to induce a greater than additive level of
expression of key mediators of atherosclerosis, including adhesion molecules, chemokines, and
components of antigen presentation pathways. While transcriptional synergy is traditionally viewed as
the product of cooperative transcription factor binding at cis-regulatory elements, it is possible for
synergism to be induced via control of rate limiting steps in the transcription cycle. These steps,
primarily RNA polymerase recruitment and pause release, are controlled by transcriptional
coactivators which are emerging as critical links between transcription factor binding and target gene
control. We hypothesize that TNFα/IFNγ induced synergistic gene expression is mediated via
kinetic regulation of the transcriptional cycle, that this involves increased recruitment of
multiple coactivators, and that synergistic gene induction can be selectively perturbed via
combination treatment with small molecule inhibitors of these coactivators. If true, we believe
this represents a promising target and therapeutic strategy in the treatment of atherosclerosis. We
plan to utilize high-throughout sequencing techniques including RNA-sequencing and Chip-
sequencing to characterize the transcriptional and epigenetic mechanisms involved in synergistic gene
induction along with a chemical biology approach to perturb likely protein mediators of this process.

## Key facts

- **NIH application ID:** 10112749
- **Project number:** 5F31HL147483-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Selma Zaki Elsarrag
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $48,100
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-12-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112749

## Citation

> US National Institutes of Health, RePORTER application 10112749, "Investigating the Regulation of TNFα/IFNγ Synergy by Transcriptional Coativators in Endothelial Cells" (5F31HL147483-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10112749. Licensed CC0.

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