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

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2021 · $368,743

## 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 development of new therapies for
AMD. A number of retinal diseases including AMD are associated with mitochondrial dysfunction5.
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-1α) plays a
major role in mitochondrial biogenesis and oxidative metabolism. It also regulates autophagy and mitophagy.
PGC-1α 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/SIRT-
1/PGC-1α is down regulated in AMD RPE. Based on our preliminary data, we hypothesize that the
repressed AMPK/SIRT1/PGC-1α pathway in RPE induces mitochondrial, autophagic dysfunction, and
increased ROS production, which result 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
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 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-1α
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-1α 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-1α 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 development of new therapeutic interventions.

## Key facts

- **NIH application ID:** 10129964
- **Project number:** 5R01EY028917-03
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Nady Golestaneh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $368,743
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129964

## Citation

> US National Institutes of Health, RePORTER application 10129964, AMPK/SIRT1/PGC-1α, a critical pathway in dry AMD (5R01EY028917-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129964. Licensed CC0.

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