# Modulation of Macrophage Function through Alternative Splicing in Cardiometabolic Diseases

> **NIH NIH K08** · NORTHWESTERN UNIVERSITY · 2020 · $162,756

## Abstract

PROJECT SUMMARY
This application is for Dr. Jennie Lin to develop her career as an academic physician-scientist focusing on the
functional genomics of cardiometabolic diseases. The career development plan includes training in mRNA
processing, macrophage biology, genome editing, and animal models of human disease, with formal mentoring
by Dr. Kiran Musunuru and Dr. Daniel Rader along with a multi-disciplinary committee of distinguished
scientists. The proposed studies and structured mentored activities will take place at the Perelman School of
Medicine at the University of Pennsylvania, which offers a remarkably rich research and training environment
that will foster Dr. Lin's professional development. The proposed research will focus on how key alternative
splicing (AS) events contribute to the pathophysiology of cardiometabolic diseases, which continue to incur
significant morbidity and mortality worldwide. Associated with chronic systemic inflammation, cardiometabolic
diseases such as atherosclerosis involve the activation of macrophages to shift toward a causally implicated
pro-inflammatory phenotype, but the mechanisms underlying this shift remain incompletely understood.
Although transcript-level changes have previously been characterized, a missing link in our understanding of
macrophage plasticity and function is whether post-transcriptional regulation is involved.! With the advent of
RNA sequencing (RNA-seq), AS − the generation of multiple different mRNA isoforms from a single gene − is
emerging as a pervasive cell-specific mechanism that can lead to human diseases if dysregulated. Because
AS plays an impactful role in cellular differentiation, it may contribute to the phenotypic plasticity of activated
macrophages and hence the pathogenesis of cardiometabolic diseases. Although few studies describe
isoform-level differences in the extremes of macrophage phenotypes, our preliminary RNA-seq studies of
activated and resting human monocyte-derived macrophages have identified more than 200 AS events for
genes associated with inflammation and cell survival. This proposal outlines a plan to study how AS events in
macrophages for two specific genes contribute to inflammatory and metabolic pathways relevant to
cardiometabolic diseases and, in particular, atherosclerosis. The first gene is PLD1, which has known roles in
lipid processing and undergoes increased inclusion of exon 16 in pro-inflammatory macrophages. The second
gene is ZC3HC1, which houses in its alternative exon 8 a genetic variant associated with coronary artery
disease. The proposed studies include two parallel aims that will investigate for each of these genes how AS
alters (1) macrophage inflammatory phenotype, (2) metabolic pathways relevant to gene function and
atherogenesis, and (3) the development and progression of atherosclerosis in vivo. In undertaking the
proposed studies and training plan, the Dr. Lin will elucidate novel mechanisms of macrophage function in the
cardiom...

## Key facts

- **NIH application ID:** 9984853
- **Project number:** 5K08HL135348-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jennie J LIn
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,756
- **Award type:** 5
- **Project period:** 2017-09-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984853

## Citation

> US National Institutes of Health, RePORTER application 9984853, Modulation of Macrophage Function through Alternative Splicing in Cardiometabolic Diseases (5K08HL135348-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9984853. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*