Blinding retinopathies constitute an urgent unmet healthcare need demanding novel therapeutic strategies. Retinal degenerative diseases are the major cause of untreatable blindness worldwide and frequently involve photoreceptor cell (PRC) death. Recently, we reported dramatic rescue of cone PRC function in the Pde6brd10/J (rd10) mouse model of retinopathy when mice were treated systemically with (+)-pentazocine ((+)- PTZ), a high affinity ligand for sigma 1 receptor (?1R). ?1R is a transmembrane protein considered a molecular chaperone involved in the ER stress response. Studies support the notion that ?1R modulates ER stress and Ca2+ signaling in retina. However, new data show that ?1R localizes also to the nuclear membrane of several retinal cell types (RGC, PRC, and Mller cells) suggesting that attenuation of ER stress may not explain entirely the mechanism(s) by which ?1R mediates retinal neuroprotection. We postulate that a novel mechanism underlying the robust retinal neuroprotection afforded by ?1R activation is modulation of the Nrf2- Keap1 pathway. Nrf2 is arguably the most important antioxidant molecule in cells because it regulates transcription of more than 500 antioxidant/cytoprotective genes. In the absence of stress, Nrf2 is retained in the cytoplasm by Keap1 and excess Nrf2 is degraded by the proteasome. However, under cellular stress, Keap1 releases Nrf2, which then translocates to the nucleus to activate ?antioxidant response elements? (ARE) of genes that encode numerous cell defense proteins and enzymes. Oxidative stress is a major pathogenic factor underlying PRC degeneration. It significantly increases binding of (+)-PTZ to ?1R. We know that (+)-PTZ treatment of rd10 mice modulates retinal Nrf2 levels, antioxidant gene expression and protein/lipid peroxidation, however we do not know whether Nrf2 is central to these retinal neuroprotective effects.
Aim 1 will test this by evaluating the extent to which Nrf2 is sufficient and essential to rd10 PRC rescue. We know that ?1R interacts functionally with Nrf2-Keap1 in primary Mller cells; however we do not know the extent to which it alters function of or interacts with proteins in the pathway.
Aim 2 will test this by evaluating the extent to which (+)-PTZ treatment alters Nrf2-Keap1 gene/protein expression, Nrf2 nuclear translocation, Nrf2 ARE activation, Keap1 inhibition, and Nrf2 proteasomal degradation in WT and ?1R-/- Mller cells and will evaluate ?1R interaction with members of the Nrf2-Keap1 pathway. Finally, we know that (+)-PTZ can rescue cone PRC in rd10 mice through post-natal day (P)42; however we do not know the extent to which (+)-PTZ treatment can delay cone death in rd10 mice beyond this age nor whether the effects are generalizable to other ?1R ligands.
Aim 3 will test this by evaluating retinal function/structure in (+)-PTZ-treated rd10 mice over an extended time course and will assess efficacy of two other ?1R ligands. In summary, promising data form the basis of our proposal, which explores a novel mechanism by which ?1R activation mediates PRC rescue and investigates the extent to which the phenomenon is sustainable and generalizable to other ?1R ligands.

Public Health Relevance

The major cause of untreatable blindness worldwide is retinal degenerative disease, frequently due to retinal ganglion or photoreceptor cell loss. Strategies to retard retinal diseases and/or to restore vision are needed desperately. This proposal examines activation of sigma 1 receptor (?1R) as a novel neuroprotective target for treatment of retinal disease and investigates whether the mechanism by which ?1R mediates neuroprotection involves modulation of the Nrf2-Keap1 pathway.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY028103-03
Application #
9769765
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
2017-09-30
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Augusta University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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