Chloroquine retinopathy is a growing health problem with the increased use of the drug to treat lupus and rheumatoid arthritis. Patients present with a loss of central vision, retinal pigmented epithelium abnormalities, and bull?s eye maculopathy. There is currently no treatment other than to stop giving chloroquine; this limits the long-term treatment of the other diseases, and the retention of chloroquine in pigmented tissues enables progressing loss of vision even after treatment has stopped. While is known to target RPE lysosomes and impair their degradative activity, it remains unclear how this leads to vision loss and how this can be treated. Recently, lysosomes have been identified as playing a critical role in intracellular and extracellular signaling, with lysosomal function extending beyond degradation to calcium signaling and the exocytosis of waste, transmitters and inflammatory signals. This proposal will determine whether these newly identified lysosomal functions are perturbed in chloroquine retinopathy. The ability of chloroquine treatment to alter lysosomal calcium signaling and exocytosis will be assayed first in our in vitro model of chloroquine retinopathy, then confirmed in our newly developed in vivo murine model of chloroquine retinopathy. The proposal will then determine whether treatments developed in recent years to enhance lysosomal pH and calcium regulation prevent the pathological changes induced by chloroquine. The restoration of lysosomal function will be determined using both in vitro and in vivo models. Finally, the ability of these treatments to prevent the loss of vision and photoreceptors in the chloroquine retinopathy mouse will be determined. The results of the project will advance our mechanistic understanding of RPE signaling in health and disease while potentially helping answer a real health need.

Public Health Relevance

Public Health Relevance Chloroquine retinopathy can lead to the loss of vision in patients, with numbers rising as the use of chloroquine increases. While the drug is known to target the lysosomes of RPE cells, it is unclear how this leads to pathology. This proposal will determine whether novel functions of RPE lysosomes like calcium signaling and secretion are impaired by chloroquine and evaluate the ability of treatments to reduce the damage.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY013434-12A1
Application #
9185763
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Neuhold, Lisa
Project Start
2002-02-01
Project End
2021-08-31
Budget Start
2016-09-30
Budget End
2017-08-31
Support Year
12
Fiscal Year
2016
Total Cost
$402,500
Indirect Cost
$152,500
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Ventura, Ana Lucia Marques; Dos Santos-Rodrigues, Alexandre; Mitchell, Claire H et al. (2018) Purinergic signaling in the retina: From development to disease. Brain Res Bull :
Lu, Wennan; Gómez, Néstor M; Lim, Jason C et al. (2018) The P2Y12 Receptor Antagonist Ticagrelor Reduces Lysosomal pH and Autofluorescence in Retinal Pigmented Epithelial Cells From the ABCA4-/- Mouse Model of Retinal Degeneration. Front Pharmacol 9:242
Gómez, Néstor Más; Lu, Wennan; Lim, Jason C et al. (2018) Robust lysosomal calcium signaling through channel TRPML1 is impaired by lysosomal lipid accumulation. FASEB J 32:782-794
Albalawi, Farraj; Lim, Jason C; DiRenzo, Kyle V et al. (2018) Effects of Lidocaine and Articaine on Neuronal Survival and Recovery. Anesth Prog 65:82-88
Ramachandra Rao, Sriganesh; Pfeffer, Bruce A; Más Gómez, Néstor et al. (2018) Compromised phagosome maturation underlies RPE pathology in cell culture and whole animal models of Smith-Lemli-Opitz Syndrome. Autophagy 14:1796-1817
Albalawi, Farraj; Lu, Wennan; Beckel, Jonathan M et al. (2017) The P2X7 Receptor Primes IL-1? and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain. Front Cell Neurosci 11:227
Lu, Wennan; Albalawi, Farraj; Beckel, Jonathan M et al. (2017) The P2X7 receptor links mechanical strain to cytokine IL-6 up-regulation and release in neurons and astrocytes. J Neurochem 141:436-448
Beckel, Jonathan M; Lu, Wennan; Civan, Mortimer M et al. (2016) Treatment of Retinal Disorders with Purinergic Drugs: Beyond Receptors. J Ocul Pharmacol Ther 32:488-489
Mitchell, Claire H; Civan, Mortimer M (2016) Introduction to Purinergic Regulation in the Eye Special Issue. J Ocul Pharmacol Ther 32:485

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