# Systems genetics approach to inflammatory mechanisms in atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $742,900

## Abstract

PROJECT SUMMARY
 This proposal is a continuation of work currently funded as a project in a PPG headed by Dr. Alan
Fogelman. The PPG must be discontinued because of a limit on the number of cycles allowed, a recent NIH
rule. During the last cycle of the grant, we studied 100 diverse strains of mice on a “humanized” hAPOE-
Leiden, hCETP background for atherosclerosis traits and for global transcriptomics and metabolomics. We
now propose to analyze the data using novel computational approaches, including integration with human data
from Genome-Wide Association Studies (GWAS) and expression datasets such as STARNET (Aim 1). We will
also continue to make our “systems genetics” data available to all interested investigators, noting that they
have now proved useful to many laboratories (Aim 1). Such data generate hypotheses which must be
experimentally tested, and we have chosen two genes/pathways based on our long-term interest in
inflammation. We will study macrophage colony stimulating factor (M-CSF) as a key regulator of macrophage
proliferation (Aim 2). We originally identified M-CSF and other CSFs as the first molecular markers of
inflammation in atherosclerosis several decades ago and have continued to study them. Our preliminary data
indicate that local M-CSF regulation is key in atherogenesis, and we will test the hypothesis and explore the
roles of the three major isoforms. We will also study the transcription factor Zhx2, which we very recently
showed to be a key driver of macrophage apoptosis in lesions (Aim 3). Our preliminary data suggest that it
interacts with cholesterol loading and other stresses which will be tested. We note that genetic ablation of
these two genes has some of the largest effects on lesion size observed. We anticipate that our studies will
provide a more comprehensive view of the pathways underlying CVD, a better integration of human and
mouse data and an improved understanding of macrophage growth and turnover in lesions. We are hopeful
that the studies will lead to new therapeutic or diagnostic advances.

## Key facts

- **NIH application ID:** 9975217
- **Project number:** 5R01HL147883-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Aldons Jake Lusis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $742,900
- **Award type:** 5
- **Project period:** 2019-07-12 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975217

## Citation

> US National Institutes of Health, RePORTER application 9975217, Systems genetics approach to inflammatory mechanisms in atherosclerosis (5R01HL147883-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975217. Licensed CC0.

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