# Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $522,087

## Abstract

PROJECT SUMMARY
 This work addresses a fundamental knowledge gap in our understanding of retinal physiology and
function that has significant bearing on the early effects of diabetes on the neural retina. Mechanistic target of
rapamycin (mTOR) kinase forms the core of two multi-protein complexes: mTOR complex 1 (mTORC1)
containing the protein Raptor, and mTORC2 complex containing the protein Rictor. The mTOR signaling
network is essential for cellular responses to trophic signals, control of cell metabolism, protein synthesis, cell
growth and cell motility. Numerous studies show a key role for mTOR complexes in neuronal function,
including axon guidance, dendrite arborization and synaptic plasticity; and numerous neurological disorders
are associated with dysfunctions of the mTOR signaling pathway. In contrast, knowledge of the roles of mTOR
complexes in retinal physiology and disease is very limited. We propose to test a distinct cell-specific role for
mTORC1 in normal retinal ganglion cell (RGC) physiology and to determine if loss of mTORC1 activity is a key
contributor to loss of RGC function and viability in diabetes. The proposed study is based on our prior findings
that diabetes causes progressive loss of total retinal protein synthesis (Fort, P.E. et al. 2014, Diabetes
63(9):3077-90) and preliminary data showing that: 1) mouse RGC exhibit a high rate of protein synthesis that is
dependent upon mTORC1 function, and 2) negating mTORC1 function in the inner retina caused eventual loss
of RGC, similar to the neurodegeneration causes by diabetes. mTORC1 activity is required for 5' cap-
dependent translation of mRNAs encoding the protein-synthetic machinery. Thus, in Specific Aim 1 we plan
to examine the role of mTORC1 activity in RGC protein synthesis and maintenance of RGC function
and viability. We will test the hypothesis that loss of mTORC1 function in RGC inhibits translation of a
discrete set of mRNAs, eventually leading to a decrease in the general protein synthetic capacity, visual
function and viability of RGC. The proposal is also based upon the premise that diabetes causes stress and
damage to the neural retina, and RGC in particular. Deactivation of mTORC1 decreases 5' cap-dependent
protein translation in response to a number of cellular stresses. Preliminary data also show that diabetes
diminishes RGC protein synthesis coinciding with increased expression of the stress-responsive inhibitor of
mTORC1 called regulated in development and DNA damage (REDD1). Thus, in Specific Aim 2 we plan to
determine if the effects of diabetes on RGC mRNA translation, function and viability are due to lack of
mTORC1 activity leading to a reduction in protein synthesis capacity. We will test the hypothesis that
maintaining mTORC1 activity and RGC protein translation during diabetes prevents RGC loss and dysfunction.
Defining the role of mTORC1 in RGC will greatly increase our knowledge of RGC physiology and of the ways
in which diabetes affects the ne...

## Key facts

- **NIH application ID:** 10072599
- **Project number:** 1R01EY031961-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Steven F Abcouwer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $522,087
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072599

## Citation

> US National Institutes of Health, RePORTER application 10072599, Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease (1R01EY031961-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072599. Licensed CC0.

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