# A transcriptional network which governs smooth muscle transition is mediated by causal coronary artery disease gene PDGFD

> **NIH NIH F32** · STANFORD UNIVERSITY · 2021 · $72,958

## Abstract

PROJECT SUMMARY OR ABSTRACT
 There are more than 160 genetic loci discovered which are associated with coronary artery disease (CAD),
yet, outside of lipid lowering therapies, the promise of these genome wide association studies (GWAS) to
identify causal genes and result in novel mechanisms for treatment has not been fulfilled. It is of critical need to
identify causal genes and characterize the cellular signaling, transcriptomic, and epigenomic regulation of
disease to discover novel treatments of CAD. The lab of my mentor has identified TCF21 as the CAD
associated gene mapped by GWAS at 6q23.2. Single cell transcriptomic analysis and disease lesion cellular
anatomy studies show that TCF21 is upregulated in SMC to promote de-differentiation, proliferation, and
migration of medial SMC into the plaque where they contribute to the protective fibrous cap. We have begun to
study the upstream regulation of TCF21 expression by the CAD associated gene encoding platelet derived
growth factor D (PDGFD). PDGFD is a member of a receptor tyrosine kinase ligand family that has been well
studied in the context of SMC phenotype and atherosclerosis and has a genetic association with CAD in
humans. Gene variants resulting in increased PDGFD expression are associated with worsened CAD. These
findings have led us to focus our attention on its determinative role in CAD. Importantly, PDGFD also directly
regulates other validated CAD genes, including CDKN2B, LMOD1, CXCL12, SMAD3, and TWIST1, thus
suggesting that it has a fundamental role in the modulation of CAD risk. We hypothesize that PDGFD promotes
CAD risk through its regulation of TCF21 and other key disease related transcription factors that mediate the
SMC phenotypic response to vascular stress. To address this hypothesis, we will use a novel Pdgfd-/- x ApoE-
/- mouse model on a smooth muscle specific reporter background in combination with state-of-the-art
technology to simultaneously evaluate single cell gene transcription and chromatin accessibility through
combination scRNAseq with scATACseq in vascular tissue. We will address our primary hypothesis with two
major specific aims, 1) Define the role of Pdgfd in regulating SMC phenotype and cellular and molecular
features of atherosclerotic vascular tissues with an in-vivo mouse model, and 2) Map the
transcriptomic program and causal epigenetic regulatory features that mediate the disease related
cellular and molecular effects of Pdgfd in-vivo in the atherosclerosis mouse knockout model. This study
will give us a fundamental understanding of how PDGFD influences SMC phenotypic response and thus CAD
risk through modulation of chromatin accessibility and transcription factor binding. Completion of this proposal
will address fundamental questions: (1) How does perturbation of Pdgfd expression affect the SMC phenotype
and molecular features of atherosclerotic vascular tissue in vivo? (2) How does Pdgfd activate epigenetic and
transcriptional processes which media...

## Key facts

- **NIH application ID:** 10313830
- **Project number:** 1F32HL160067-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Chad S Weldy
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $72,958
- **Award type:** 1
- **Project period:** 2021-08-31 → 2023-08-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313830

## Citation

> US National Institutes of Health, RePORTER application 10313830, A transcriptional network which governs smooth muscle transition is mediated by causal coronary artery disease gene PDGFD (1F32HL160067-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10313830. Licensed CC0.

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