# AMPK/SIRT1/PGC-1α, a critical pathway in dry AMD

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2021 · $41,340

## Abstract

ABSTRACT
Age-related macular degeneration (AMD) is the major cause of blindness in people over age 55 in the U.S. and
the developed world. One of the two forms of AMD is the “dry” form, for which currently there are no effective
treatments. Consequently, there is an unmet medical need for the development of new therapies for AMD. A
number of retinal diseases, including AMD, are associated with mitochondrial dysfunction. Dysfunctional
mitochondria induce increased levels of reactive oxygen species (ROS) and defective metabolic activity.
Autophagy loss also results in mitochondrial dysfunction and is suggested to increase susceptibility to oxidative
stress and AMD. We have recently shown dysfunctional autophagy, increased ROS, and dysfunctional
mitochondria in RPE derived from AMD donor eyes. However, the underlying mechanisms inducing these
defective metabolic homeostases leading to AMD remain unknown. The Peroxisome proliferator-activated
receptor-gamma coactivator (PGC)-1alpha (PGC-1) plays a major role in mitochondrial biogenesis and
oxidative metabolism. It also regulates autophagy and mitophagy. PGC-1 activity is stimulated by two main
factors: AMP-activated protein kinase (AMPK) and NAD+ - dependent deacetylase, SIRT1. Preliminary evidence
from our laboratory suggests that the AMPK/SIRT1/PGC-1 is downregulated in AMD RPE. Based on our
preliminary data, we hypothesize that the repressed AMPK/SIRT1/PGC-1 pathway in RPE induces
mitochondrial, autophagic dysfunction, and increased ROS production, which results in abnormal metabolic
activity, lipid and glycogen accumulation, and drusen formation, leading to the AMD pathophysiology. To test
our hypothesis, we have developed an inexhaustible AMD in vitro disease model by isolating native RPE from
AMD donors’ eyes, followed by the generation of iPSC and their subsequent differentiation into RPE (AMD RPE-
iPSC-RPE). We have also generated iPSC from RPE of age-matched normal donors (Normal RPE-iPSC-RPE)
that serve as the control. We confirmed that the AMD RPE-iPSC-RPE mimic the disease phenotypes of their
parental donors, the primary AMD RPE, which validates our model. Additionally, we established an animal model
to test the role of PGC-1 repression on RPE and retinal health and observed RPE and photoreceptor
degeneration. We propose two aims: Aim1 will test the role of AMPK/SIRT-1/PGC-1 pathway inhibition in dry
AMD using our established in vitro model from AMD donors and AMD patients. Aim2 will investigate the cellular
and molecular mechanisms of PGC-1 actions on RPE and retinal health in a mouse model. Ultimately, these
studies will provide insight into the molecular mechanisms of dry AMD and may facilitate new therapeutic
interventions.

## Key facts

- **NIH application ID:** 10355656
- **Project number:** 3R01EY028917-03S1
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Nady Golestaneh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $41,340
- **Award type:** 3
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355656

## Citation

> US National Institutes of Health, RePORTER application 10355656, AMPK/SIRT1/PGC-1α, a critical pathway in dry AMD (3R01EY028917-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10355656. Licensed CC0.

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