# The role of TWIST1 in smooth muscle cells during atherosclerosis

> **NIH NIH K08** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $158,441

## Abstract

The purpose of this award is to provide Dr. Robert Wirka protected time, allowing him to obtain the training
necessary to become an independent investigator using human genetic findings to define novel mechanisms
driving coronary artery disease (CAD). Career development activities are designed to strengthen Dr. Wirka's
skills in three key areas necessary for achieving this research paradigm: i) Linking disease-associated variation
to causal genes; ii) Determining how causal genes affect cellular and vascular biology; and iii) Defining the
molecular pathways and networks affected by causal genes. His mentor, Dr. Quertermous, will guide and
monitor his progress towards independence. During atherosclerosis, vascular smooth muscle cells (SMCs) de-
differentiate, proliferate and migrate into the lesion in a process known as “phenotypic modulation”. In a recent
first-author paper in Nature Medicine, Dr. Wirka generated single-cell gene expression datasets from diseased
mouse and human arteries and characterized the process of SMC phenotypic modulation in unprecedented
detail. In the current proposal, Dr. Wirka has used these data to identify the transcription factor TWIST1 as a
potential novel regulator of SMC phenotypic modulation. In pathway analysis of the mouse and human gene
expression data, TWIST1 is strongly predicted to promote SMC phenotypic modulation. Consistent with this
predicted role, TWIST1 gene expression increases in SMCs during phenotypic modulation in the mouse and
human single-cell data, and preliminary studies show that TWIST1 inhibits expression of SMC differentiation
markers. Importantly, TWIST1 is also strongly associated with multiple vascular diseases, including CAD, in
human genetic studies. The proposed studies will determine the role of TWIST1 in vascular SMCs during
disease, and determine the cellular and molecular mechanisms by which this occurs. In Aim 1, SMC-
specific conditional Twist1 knockout mice will be used to determine how Twist1 affects SMC phenotype within
the atherosclerotic lesion: i) assessment of single-cell gene expression will be used to determine the effect of
SMC-specific Twist1 knockout on the ability of SMCs to undergo phenotypic modulation during disease and to
map the molecular pathways affected by Twist1, and ii) in situ studies of the diseased artery wall will examine
the effect of SMC-specific Twist1 knockout on classical aspects of lesion phenotype and the contribution of
SMCs to the lesion. In Aim 2, cultured human coronary artery SMCs (HCASMCs) will be used to determine the
cellular and molecular effects of TWIST1: i) the effect of TWIST1 perturbation on SMC phenotypes relevant to
atherosclerosis such as differentiation, proliferation, migration, invasion, and cell death will be determined, and
ii) the detailed molecular mechanism by which TWIST1 inhibits expression of the SMC differentiation marker
ACTA2 will be explored. These studies will determine the cellular and molecular mechanisms by w...

## Key facts

- **NIH application ID:** 10355544
- **Project number:** 5K08HL152308-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Robert Wirka
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $158,441
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355544

## Citation

> US National Institutes of Health, RePORTER application 10355544, The role of TWIST1 in smooth muscle cells during atherosclerosis (5K08HL152308-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10355544. Licensed CC0.

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