# Tspan14 expression and function in cardiovascular disease

> **NIH NIH R00** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Genetic predisposition is a significant risk factor for coronary artery disease (CAD), the leading cause of
mortality. Most CAD risk variants identified in genome-wide association studies (GWAS) are in noncoding
DNA, which poses a major challenge in identifying the target genes in the disease-critical cell types. Using the
Activity-by-Contact Model to predict cell type-specific gene-enhancer pairs, we identified cis-regulatory
elements in the chromosome 10q23 locus harboring multiple CAD-risk variants. Our preliminary studies show
that these enhancers in the 10q23 locus regulate tetraspanin 14 (TSPAN14) gene expression, specifically in
vascular endothelial cells (ECs) and monocytes. We have established strong population genetics evidence that
higher TSPAN14 expression reduces CAD risk and there is a consistent protective effect for the minor alleles
at the lead variants. TSPAN14 is an adaptor protein that aids in trafficking proteins like ADAM10, a Notch
receptor activator, to the plasma membrane. The role of Notch pathway activation imparted by this TSPAN14-
ADAM10 interaction in CAD pathogenesis has not been explored. In addition, we performed RNA-seq and
identified differentially expressed genes in TSPAN14-deficient cells that will help discover Notch-independent
TSPAN14 functions. These findings provide a premise for the central hypothesis that the genetic regulation of
TSPAN14 by variations in the 10q23 enhancer sequences affects CAD pathogenesis through Notch-
dependent and -independent mechanisms in vascular ECs and monocytes. In Aim 1, Dr. Lee-Kim will
determine the cell type-specific effect of 10q23 enhancer sequence variations on TSPAN14 expression
regulation. In Aim 2, she will determine the Notch-dependent effects of TSPAN14 expression in vascular and
immune cells. In Aim 3, she will characterize the Notch-independent TSPAN14 functions in vascular and
immune cells. The results from these studies will functionally validate the gene target for noncoding variants
associated with CAD-risk in the disease-relevant cell types and elucidate how TSPAN14 functions in CAD
pathogenesis. These studies will be conducted under the supervision of mentors, Dr. Rajat Gupta and Dr.
Stephen Blacklow, and an advisory committee dedicated to Dr. Lee-Kim’s success. With additional support
from the MOSAIC UE5 awardee sponsored professional development opportunities, continued training in the
K99 phase will prepare Dr. Lee-Kim for successful transition to independence.

## Key facts

- **NIH application ID:** 11134863
- **Project number:** 4R00HL163411-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Vivian Lee-Kim
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2024-09-16 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11134863

## Citation

> US National Institutes of Health, RePORTER application 11134863, Tspan14 expression and function in cardiovascular disease (4R00HL163411-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11134863. Licensed CC0.

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