# Novel pathways controlling macrophage inflammation and resolution in atherosclerosis

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2020 · $720,981

## Abstract

Summary
In-spite of effective strategies for lowering cholesterol, atherosclerosis and associated cardiovascular diseases
remain a major global health burden. Work in recent years has highlighted the exciting therapeutic potential for
interventions that reduce inflammation, as well as the need for identifying novel and selective targets. Our long
term goal is to understand how lipid metabolism and inflammation interact, and how these interactions can be
useful therapeutically. The objective of the current research proposal is to determine the role of the transcription
factor Nuclear factor erythroid 2 related factor-1 (Nrf1; also known as Nfe2L1) in linking these two processes.
The central hypothesis is that Nrf1 in the macrophage is a critical factor for preventing chronic inflammation and
maintaining cholesterol homeostasis, and that enhancing these actions of Nrf1 may be beneficial in
atherosclerosis. This is based on compelling new preliminary data showing that Nrf1 is activated in macrophages
in response to inflammatory stimuli and is necessary for the expression of lipid metabolism pathway genes that
are crucial for proper resolution of the inflammatory state. Previous results also showed that deletion of Nrf1
drastically impairs cellular cholesterol homeostasis.The rationale for the proposed research is that understanding
the function and mechanism of macrophage Nrf1 may provide important insight into regulation of macrophage
inflammation and resolution in general and reveal a novel therapeutic target for the treatment of atherosclerosis.
The central hypothesis will be tested by pursuing three specific aims: 1) Examine the function of Nrf1 in
macrophages; 2) Elucidate the molecular mechanism of Nrf1 action in macrophages; and 3) Explore the
importance of macrophage-Nrf1 in atherosclerosis in-vivo. Under the first aim, tissue-specific inducible deletion
models established and tested in the applicant's lab will be used for a thorough characterization of the function
of Nrf1 in inflammatory output, lipid metabolism and resolution of inflammation. This aim will also explore the
impact of cholesterol on Nrf1 function, and the reciprocal role of Nrf1 in regulating cholesterol homeostasis in
macrophages. In the second aim, immunoprecipitation of readily available tagged protein coupled to DNA
sequencing and MS/MS analysis will identify, protein interactors and post translational modifications of Nrf1
potentially mediating its function. The third aim will test the impact of Nrf1 deficiency and overexpression on
atherosclerosis in-vivo using already established Western-diet fed Ldlr-deficient mice with either macrophage
specific deletion of Nrf1, or adeno-associated-virus (AAV) mediated macrophage specific overexpression of Nrf1.
The approach is innovative because it attempts to overcome issues of pro-resolving mediator delivery by using
naturally existing systems within macrophages. The proposed research is significant, because current
approaches ...

## Key facts

- **NIH application ID:** 9985167
- **Project number:** 5R01HL148137-02
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** GOKHAN S HOTAMISLIGIL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $720,981
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985167

## Citation

> US National Institutes of Health, RePORTER application 9985167, Novel pathways controlling macrophage inflammation and resolution in atherosclerosis (5R01HL148137-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9985167. Licensed CC0.

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