# MIF and Cardiovascular Inflammation

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2022 · $373,750

## Abstract

Project Summary
Alzheimer’s Disease (AD) is an aging-associated disease defined by progressive neurodegeneration,
neuroinflammation, and the presence of protein aggregates consisting of amyloid β (Aβ) and
hyperphosphorylated tau. However, the molecular details of AD pathogenesis still need to be clarified.
Interestingly, AD is associated with several neuronal abnormalities in energy metabolism such as mitochondrial
dysfunctions and decline in glucose uptake, and defects in cholesterol metabolism and Ca2+ homeostasis. Our
studies revealed that an energy sensor AMP-activated protein kinase (AMPK) regulates glucose transporter
trafficking to modulate energy metabolism under both physiological and pathological conditions. We further
identified a cytokine, macrophage migration inhibitory factor (MIF), which is one critical factor responsible for
cardiac AMPK signaling regulation of energy metabolism in response to pathological stress. More
epidemiological studies have reported that metabolic syndrome and cardiovascular diseases are risk factors
for cognitive impairment and sporadic AD since metabolic disturbances and alterations in redox homeostasis
increase the chances of cognitive decline and AD. AMPK signaling regulates pathways that control oxidative
stress-related vascular inflammation and modulates tau protein phosphorylation and amyloidogenesis. We
have found that an aging-related reduction in the MIF-AMPK signaling cascade is an important contributing
factor leading to increased sensitivity to reactive oxygen species (ROS) from mitochondrial dysfunctions under
pathological stress conditions. Considering the properties of MIF-AMPK signaling cascade in energy
metabolism and inflammatory response, and age-related impaired AMPK signaling pathways in response to
stress. We hypothesize that age-related AD is associated with a decline in the ability of the brain to render the
MIF-AMPK signaling cascade active in response to aging caused pathological stress, thus resulting in
exacerbated cerebral injury. We will test this hypothesis with the specific aim: define the role of the MIF
receptor in age-related impaired AMPK signaling in response to pathological stress in AD and evaluate the
capability of small-molecule MIF agonist to improve MIF-AMPK activation during AD pathogenesis. In this
manner, we seek to advance our understanding of the mechanisms behind aging-related alterations in AMPK
signaling pathways in response to alterations in metabolic homeostasis and neuroinflammation that occurred
during AD pathogenesis.

## Key facts

- **NIH application ID:** 10496927
- **Project number:** 3R01HL158515-02S1
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Ji Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $373,750
- **Award type:** 3
- **Project period:** 2021-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496927

## Citation

> US National Institutes of Health, RePORTER application 10496927, MIF and Cardiovascular Inflammation (3R01HL158515-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10496927. Licensed CC0.

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