# Inflammaging and Diabetic Retinopathy

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2024 · $469,854

## Abstract

PROJECT SUMMARY
Diabetic retinopathy (DR) is a neurovascular complication of diabetes mellitus and the leading cause of blindness
in adults. Prevention of hyperglycemia-induced retinal microvascular dysfunction remains one of the therapeutic
goal to preserve vision in diabetic patients. Recent insights from our group and others have shown that
hyperglycemia results in retinal endothelial cells (RECs) stress-induced premature senescence (SIPS), a
senomorphic process characterized by the acquisition of the so-called senescence-associated secretory
phenotype (SASP) and linked to chronic inflammation. The exact causes and consequences of this mechanism
and its relative impact in DR are presently unknown and understudied. Evidence provided by the literature and
our own preliminary results suggests that central to the development of SIPS is the increased expression and
activity of the histone deacetylase 6 (HDAC6) paralleled by loss of the NAD+-dependent histone deacetylase
SIRT-1. This imbalance results in a switch in cell acetylome that has proven to result in mitochondrial dysfunction
and has been linked to the pathogenesis of a number of pathologies including diabetic complications and
neurodegeneration. In addition, we have found that exosomes isolated from diabetic RECs could propagate
senomorphic and pro-inflammatory signals to neighboring vascular cells and to recruited neutrophils to promote
degenerative changes such as netosis. Our overall working hypothesis is that altered SIRT-1-HDAC6 balance
leads to exosomes-mediated retinal vascular SIPS and strategies aimed at halting this process could have
therapeutic value to prevent/combat diabetic retinal microangiopathy and, potentially, DR. We have designed
studies to validate our working hypothesis, but also aimed at extending the present knowledge of the molecular
and cellular mechanisms promoting microangiopathy in the diabetic retina. Our aims are: Aim1 To investigate
the contribution of HDAC6 to retinal vascular senescence, diabetic microangiopathy and DR. Aim2 To
investigate the effects of enhancing/rescuing SIRT1 on vascular senescence, diabetic retinal microangiopathy,
and DR. The results of our proposed studies will unveil an important pathogenic hub by confirming the existence
of a negative feedback between HDAC6 and SIRT-1 and by revealing specific acetylome and exosomes
signatures, thus enabling the identification of new diagnostic and therapeutic tools for retinal microangiopathy
and DR.

## Key facts

- **NIH application ID:** 10812925
- **Project number:** 1R01EY034684-01A1
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** MANUELA BARTOLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $469,854
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812925

## Citation

> US National Institutes of Health, RePORTER application 10812925, Inflammaging and Diabetic Retinopathy (1R01EY034684-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10812925. Licensed CC0.

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