# RAGE/mDia1, Macrophage Trafficking and Inflammation in Regression of Diabetic Atherosclerosis

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $622,217

## Abstract

Summary
Cardiovascular disease (CVD) represents the major cause of morbidity and mortality in patients with diabetes.
Despite aggressive management of levels of lipids and glucose, both types 1 and 2 diabetic patients exhibit
earlier onset and more extensive atherosclerotic lesions than non-diabetic subjects, and the response to lipid-
lowering strategies is significantly less robust than the beneficial effects noted in non-diabetic subjects.
Preclinical studies in diabetic animals have shown accelerated progression and impaired regression of
atherosclerotic plaques, as well as increased retention of macrophages (MØs) in plaques. We will focus on
diabetes-driven mechanisms linked to impaired atherosclerosis regression and the specific role of MØ
perturbation. Our proposed studies are built on the discovery that transplantation of aortic arches from Ldlr-/-
mice into diabetic mice deficient in RAGE or its cytoplasmic domain binding partner, DIAPH1, required for
RAGE signaling, display significantly improved plaque regression, independent of changes in plasma glucose
or lipid levels, compared to wild-type diabetic mice. Our earlier studies demonstrated that activation of RAGE is
a critical component of the vessel wall response to hyperglycemia and that RAGE-driven mechanisms
accounted for the observed acceleration and progression of atherosclerosis. In this application, using models
of hyperglycemia and insulin resistance (IR), we will test the hypothesis that the consequences of
hyperglycemia and RAGE/DIAPH1-dependent mechanisms in MØs modulate MØ trafficking (recruitment &
retentions/stasis), MØ inflammatory polarization and MØ metabolism and oxidative stress, mechanisms which
converge to suppress regression of established atherosclerotic plaques in diabetes. We will test novel
pharmacological antagonists of RAGE/DIAPH1 in our murine model of diabetic atherosclerosis regression.
These studies will provide novel insights into diabetes specific mechanisms that promote MØ accumulation
and impair regression, and foster the development of novel therapeutic adjuncts for diabetic atherosclerosis.

## Key facts

- **NIH application ID:** 9842564
- **Project number:** 5R01HL132516-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Ravichandran Ramasamy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $622,217
- **Award type:** 5
- **Project period:** 2016-12-09 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842564

## Citation

> US National Institutes of Health, RePORTER application 9842564, RAGE/mDia1, Macrophage Trafficking and Inflammation in Regression of Diabetic Atherosclerosis (5R01HL132516-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842564. Licensed CC0.

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