# Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $416,932

## Abstract

Atherosclerosis (AS) remains the leading cause of death world-wide and it is often associated with
dyslipidemia, oxidative stress and mitochondrial dysfunction. Macrophage is a type of innate immune cell that
plays a critical role in the development of AS. Unrestricted uptake of oxidized LDL (oxLDL) by macrophages
leads to accumulation of lipid intracellularly and foam cell formation, which is a hallmark of early stages of AS.
OxLDL uptake is mainly mediated by CD36, a scavenger receptor highly expressed on the macrophage
surface. One major problem is that oxLDL leads to up-regulation of CD36 expression through a transcription
factor PPARγ, resulting in a positive feedback mechanism to further enhance CD36-mediated oxLDL uptake.
Defining the novel regulator of this process is the central goal of this multi-PI proposal. Recent published and
preliminary studies showed that Pim1, a conserved serine/threonine kinase regulates CD36 transcription. In
addition, genetic ablation of pim1 gene in macrophages resulted in a reduction in PPARγ pathway as well as
the downstream targets involved in fatty acid metabolism and mitochondrial oxidative phosphorylation. We thus
hypothesized that Pim1 kinase coordinates PPARγ activation/CD36 expression and mitochondrial functions to
regulate fatty acid metabolism and immune activation in macrophages. Continuous stimulation of Pim1 kinase
in macrophages contributes to pro-atherogenic phenotypes and AS. Specific aim 1 will determine the
molecular mechanism by which Pim1 kinase in macrophages coordinates PPARγ activation/CD36 expression
and mitochondrial function to modulate fatty acid metabolism. We will use a combination of genetically
modified macrophages, biochemical, immunological and ex vivo cell metabolic studies to determine the
mechanisms by which Pim1 kinase regulates fatty acid metabolism through the PPARγ/CD36 pathway; and to
determine the mechanisms by which Pim1 kinase regulates mitochondria morphology through Drp-1 and
define the impact on mitochondria fatty acid oxidation, oxidative phosphorylation and ROS production. Aim 2
will test the hypothesis that inactivating Pim1 kinase in vivo suppresses the development of AS. Using the
genetic pim1 ablation model and minipump infusion of the Pim inhibitor AZD1208, we aim to test the
hypothesis that Pim1 activity is indispensible for diet-induced AS in mice; and to test the hypothesis that
pharmacologic inhibition of Pim1 suppresses PPARγ/CD36 pathway and reprograms macrophage
mitochondria toward ROS production under atherogenic conditions; and test the hypothesis that Pim1
regulates bone marrow-monocyte-macrophage differentiation lineage under atherogenic conditions. By
elucidating the molecular mechanisms by which Pim1 kinase coordinates fatty acid metabolism and
mitochondrial functions to control macrophage activation under atherogenic conditions, we expect to gain
crucial knowledge on novel lipid metabolism regulators and provide new treatment strategies agai...

## Key facts

- **NIH application ID:** 10372226
- **Project number:** 5R01HL153397-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** WEIGUO CUI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $416,932
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372226

## Citation

> US National Institutes of Health, RePORTER application 10372226, Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages (5R01HL153397-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10372226. Licensed CC0.

---

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