# Strategies and Functional Outcomes of Enhancing in Vivo Production of Soluble Rage Isoforms

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $613,936

## Abstract

Project Summary /Abstract
Activation of RAGE (receptor of advanced glycation endproducts (AGEs)), via binding of AGEs and other
ligands, modulates the development and progression of diabetic complications through persistent and cyclic
activation of nuclear factor-ΚB. Targeting RAGE directly as a therapeutic strategy has largely been
unsuccessful. However, RAGE signaling can be interrupted, in vivo, by ADAM10 (a disintegrin and
metalloproteinase 10) directed proteolytic cleavage of the RAGE ectodomain, and thus creating a soluble
isoform of RAGE (sRAGE) that is released from the cell and appears into the circulation. Maintaining high
levels of circulating sRAGE is advantageous as sRAGE will sequester RAGE ligands and prevent RAGE cell
signaling. Our long-term goal is to identify strategies for the prevention and treatment of diabetic complications.
Using aerobic exercise, we have elucidated a mechanism for ADAM10 upregulation to increase RAGE
shedding. Aerobic exercise presents a unique model for mechanistic study of RAGE shedding as muscle
contraction provides stimuli for tissue remodeling and resolution of the metabolic milieu that drives
inflammation. Our central hypothesis is that skeletal muscle is a quantitatively important source of sRAGE
appearance in the circulation and maintenance of healthy levels of total sRAGE promotes cardiometabolic
health. The rationale is that once the mechanisms of ADAM10 activation and sRAGE generation are
elucidated, progress towards the prevention and treatment of diabetic complications may be possible.
Compelled by noteworthy preliminary data, we propose three specific aims to pursue our central hypothesis:
(1) we will test the effects of acute and chronic exercise in generating sRAGE isoforms (2) we will determine
the effects of acitretin therapy on RAGE mediated inflammation and (3) we will explore new protective effects
of sRAGE in the microvasculature. The work is innovative because the study of RAGE ectodomain shedding in
human skeletal muscle challenges the current understanding of AGE/RAGE biology and the known behavior of
ADAM10 activity. At the completion of these studies, it is our expectation that we will have identified a novel
mechanism of ADAM10 activation and an important tissue source of sRAGE production. Ultimately, such an
insight has the potential to improve the prevention and therapeutic management of diabetes and its
complications, thus reducing the financial and social burden that affects the ~347 million people worldwide with
diabetes.

## Key facts

- **NIH application ID:** 9934871
- **Project number:** 5R01DK109948-06
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** JACOB M HAUS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $613,936
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934871

## Citation

> US National Institutes of Health, RePORTER application 9934871, Strategies and Functional Outcomes of Enhancing in Vivo Production of Soluble Rage Isoforms (5R01DK109948-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934871. Licensed CC0.

---

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