Retinal degeneration is a major cause of blindness in the USA and often results from a combination of environmental and genetic influences. While progress has been made in identifying some of the pathological factors, a better understanding of how defects lead to disease will result in better treatment. This proposal is based upon the hypothesis that the alkalization of lysosomes in RPE cells contributes to retinal degeneration. Lysosomal alkalinization is known to impede degradation and increase the accumulation of waste material. However, new findings suggest additional ways that alkalinized lysosomes can contribute to retinal degenerations, and these will be confirmed and extended. For example, oxidized lipids are known to escalate degeneration, and new data showing that lysosomal alkalinization leads to increase lipid oxidation in vitro and in vivo will be probed. Microglia and macrophages are also implicated in the disease process, and experiments will probe how lysosomal alkalinization leads to the release of cytokines and ATP, chemoattractants that can recruit the monocytes to RPE cells. This proposal will also update a model of chloroquine retinopathy and demonstrate that lysosomal alkalinization is sufficient to activate molecular and protein markers of retinal degeneration. The chloroquine approach will be applied to genetic models of retinal degenerations to test if lysosomal alkalinization acts synergistically with genetic defects to speed the onset and increase severity of the pathologies. Finally, acidic nanoparticles will be used to reacidify compromised RPE lysosomes in vivo and prevent the loss of photoreceptors in a model of retinal degeneration. In summary, this proposal will examine the mechanisms linking lysosomal alkalinization to disease, demonstrate that lysosomal alkalinization combines with genetic defects to increase pathology, and show that reacidifying lysosomes with acid nanoparticles can prevent the loss of photoreceptors.

Public Health Relevance

Retinal degenerations are major causes of blindness in the USA. This project will investigate how defective lysosomes in RPE cells can lead to damage in these diseases and test the ability of a new treatment to prevent this loss of sight.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01EY013434-11A1
Application #
8718592
Study Section
(DPVS)
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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