# mTORC1-TFEB pathway in degeneration of the RPE

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $370,636

## Abstract

The long-term goal of this project is to elucidate the mechanisms by which membrane trafficking is regulated in
retinal pigment epithelium (RPE) cells, and to understand the role of defects in this regulation in retinal
diseases including age-related macular degeneration (AMD). The RPE is responsible for the removal of daily
shed photoreceptor outer segments (POS) by phagocytosis, which activates tightly controlled processes of
membrane trafficking and organelle transport. In our published and preliminary studies, we found that
phagocytosis activated signaling pathway mediated by the mechanistic target of rapamycin (mTOR). Under
physiological conditions, mTOR activation was transient. Aging and degeneration, however, rendered mTOR
activation to become prolonged after morning burst. In our newly developed murine model of RPE-specific
deletion of mTORC1 upstream suppressor TSC1, constitutively high mTOR activity led to RPE and
photoreceptor degeneration, likely caused by deregulated membrane trafficking and delayed POS degradation.
We further identified VPS11, a key component of the membrane tethering complexes, was downregulated in
TSC1-deficient RPE cells possibly due to inhibition on the transcription factor EB (TFEB). Based on those
novel findings, we hypothesize that hyperactivation of mTORC1 can cause RPE and photoreceptor
degeneration due to defective membrane trafficking. Enhancing TFEB-mediated expression of RPE
trafficking proteins can restore the cellular functions and prevent the degenerative phenotype in retina
of TSC1RPE mice. The hypothesis will be tested by three specific aims. Aim 1 is to further characterize the
retinal phenotype of mice with conditional knockout of TSC1 in the RPE. Aim 2 is to determine whether
overactivation of mTOR inhibits RPE intracellular trafficking and membrane fusion by inhibiting TFEB-mediated
VPS11 expression. Aim 3 is to determine whether TFEB gene therapy can prevent or rescue RPE
degeneration. Results from the proposed studies are expected to further establish the critical roles of mTOR in
controlling the RPE and photoreceptor interaction. Although anti-VEGF therapy has achieved unprecedented
success, the majority of AMD patients have the atrophic form of the disease whose etiology is still largely
unknown and treatment options are very limited. Identifying novel targets downstream of mTOR in
degenerating RPE cells can facilitate the design of therapeutic strategies to prevent or at least delay the
disease progression at early stage of AMD.

## Key facts

- **NIH application ID:** 10004632
- **Project number:** 5R01EY026999-05
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Yan Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,636
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004632

## Citation

> US National Institutes of Health, RePORTER application 10004632, mTORC1-TFEB pathway in degeneration of the RPE (5R01EY026999-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004632. Licensed CC0.

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