# Molecular Mechanisms of Diabetic Retinal Ganglion Cell Dysfunction and Neurovascular Crosstalk in Early Diabetic Retinopathy

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2020 · $199,413

## Abstract

PROJECT SUMMARY/ABSTRACT
Diabetic retinopathy (DR) represents the leading cause of blindness in working-age adults, with vision loss due
to sequelae of proliferative retinal neovascularization and diabetic macular edema (DME). As such, it has
traditionally been considered a disease of the retinal microvasculature. However, diabetes is also associated
with retinal neuronal damage and diabetic patients exhibit visual functional deficits prior to the onset of
clinically-apparent retinopathy. Increasing evidence from both diabetic patients and mouse models has further
demonstrated progressive inner retinal neuronal loss which is present early in the course of the disease,
preceding clinically-identified retinal vascular changes. The molecular mechanisms of early diabetic retinal
neurodegeneration are unknown, although mitochondrial dysfunction has been implicated in DR, primarily in
studies of whole retina and vascular endothelial cells. Mitochondrial dysfunction has also been shown to play
a critical role in the pathogenesis of neurodegeneration in Parkinson’s disease (PD), with rare hereditary forms
of PD associated with mutations in the mitophagy genes PINK1 and parkin. The laboratory of Dr. Ted
Dawson, the principal investigator’s primary mentor, has identified a novel parkin-interacting substrate, PARIS,
which regulates mitochondrial biogenesis via repression of PGC1a and has demonstrated that loss of
dopaminergic neurons in the setting of parkin deficiency is driven primarily by impairments in mitochondrial
biogenesis via the parkin/PARIS/PGC1a pathway. The role of mitochondrial biogenesis and its balance with
mitophagy in retinal ganglion cells (RGCs) under diabetic conditions has not been explored. The hypotheses
of this project are that (1) diabetes directly induces RGC dysfunction and loss via perturbations in the
parkin/PARIS/PGC1a pathway of mitochondrial mass regulation, and that (2) dysfunctional RGCs in this
setting secrete factors that directly affect the retinal vasculature. Under the additional mentorship of Dr. Don
Zack and Dr. Gerard Lutty, and within the rich collaborative environment of the Johns Hopkins University
School of Medicine, these hypotheses will be tested using in vitro approaches with primary cultured murine
RGCs and hESC-derived RGCs, and in an in vivo mouse model of diabetes (streptozocin). The principal
investigator is an MD/PhD clinician-scientist, who completed her training as a Vitreoretinal Surgeon, and now
regularly cares for patients with vision loss due to diabetic retinal disease despite currently-available
treatments, motivating her to investigate novel molecular pathways of disease pathogenesis. She is currently
in year one of support from the Johns Hopkins Department of Ophthalmology K12 grant. Building upon the
foundation of her PhD research, this K08 award will facilitate the additional expertise and training she needs to
address her hypotheses and eventually transition to a position as an independent...

## Key facts

- **NIH application ID:** 9873035
- **Project number:** 5K08EY029766-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mira Menon Sachdeva
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,413
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873035

## Citation

> US National Institutes of Health, RePORTER application 9873035, Molecular Mechanisms of Diabetic Retinal Ganglion Cell Dysfunction and Neurovascular Crosstalk in Early Diabetic Retinopathy (5K08EY029766-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873035. Licensed CC0.

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