There are now almost 200 genes and chromosomal loci which have been identified as causing some form of inherited retinal degeneration. Irrespective of the primary mutation or cause, all of these diseases are thought to share a major common event. This is """"""""oxidative stress"""""""" as a result of a chronic or acute rise in Reactive Oxygen Species (ROS). Antioxidants and over-expression of antioxidant enzymes have been shown to inhibit the progression of many retinal diseases. Inorganic cerium oxide nanoparticles (nanoceria) are antioxidants which mimic the activities of catalase and super oxide dismutase by catalytically scavenging ROS and have been shown to prevent peroxide induced blindness in rats. We think of the nanoceria as being analogous to an aspirin for blindness in that they won't cure the primary defect but will decrease the severity of the disease. We have hypothesized, that because ROS represent a node common to many inherited blinding diseases, they also represent an """"""""Achilles'heel"""""""" which can be specifically targeted using ROS-scavenging nanoceria. As a component of that strategy, nanoceria will be used in this study to inhibit the inherited programmed death of photoreceptors in a mouse strain, tubby, which is a phenotypic model for Usher's Syndrome.
Specific Aim 1 will test the hypothesis that the nanoceria particles will destroy ROS and, by decreasing oxidative damage in retinal neurons, will inhibit retinal degeneration induced by the tubby mutation. The hypothesis that nanoceria will act synergistically with sulphoraphane (Specific Aim 2) or with the overexpression of the human thioredoxin transgene (Specific Aim 3) to provide enhanced and prolonged protection of the photoreceptor cells in the tubby retina will also be tested. Our preliminary and published data support the effectiveness of each of these therapies when used alone in the tubby mouse. The mechanisms by which the nanoceria function in the tubby mouse alone, and in combination with sulphoraphane, or the Trx transgene, will be identified by the following methods. Superoxide radicals in the retina will be assessed using a hydroxyethidine assay whereas H20 2 will be assayed with 2',T-dichlorodihydro- fluorescein-diacetate. ROS-induced damage will be visualized with antibodies against products of ROS activity including acrolein, nitrotyrosine and 8-hydroxy-2-deoxy-guanosine. The effects of the nanoceria on neuroprotective pathways will be analyzed by Western blots, cDNA micro arrays, and Real Time-PCR. Quantitative histology, using bright field microscopy on hematoxylin and eosin stained retinal sections, will be used to evaluate the morphological preservation of photoreceptor cells. Retinal function will be determined by electroretinography. We currently have large colonies of both the tubby and the Trx-tubby mice and will be able to complete the specific aims within two years. The successful achievement of our objectives should be directly relevant to most forms of inherited blindness in mice. The nanoceria are expected to function in humans as they do in other mammals and therefore should preserve vision and prevent blindness in humans.

Public Health Relevance

There are millions of people in the USA who have a neurodegenerative disease of the retina such as Age Related Macular Degeneration, Retinitis Pigmentosa or Diabetic Retinopathy. Additional millions have degeneration of neurons elsewhere in the CNS such as occurs in Alzheimer Disease, Parkinson Disease, Dementia, etc. Reactive Oxygen Species are common causative factors thought to be involved in all of these diseases. Our published data demonstrate that our rare earth element inorganic cerium oxide nanoparticles (nanoceria) prevent Reactive Oxygen Species-induced retinal degeneration in rats. Prevention of inherited retinal degeneration by these nanoceria, in the two selected mouse mutants will strongly support the conclusion that they can also preserve vision and prevent blindness in humans.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018724-02
Application #
7895588
Study Section
Special Emphasis Panel (ZRG1-NANO-M (01))
Program Officer
Neuhold, Lisa
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$363,220
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Cai, Xue; McGinnis, James F (2016) Diabetic Retinopathy: Animal Models, Therapies, and Perspectives. J Diabetes Res 2016:3789217
Cai, Xue; Seal, Sudipta; McGinnis, James F (2016) Non-toxic retention of nanoceria in murine eyes. Mol Vis 22:1176-1187
Cai, Xue; Chen, Lijuan; McGinnis, James F (2015) Correlation of ER stress and retinal degeneration in tubby mice. Exp Eye Res 140:130-138
Walkey, Carl; Das, Soumen; Seal, Sudipta et al. (2015) Catalytic Properties and Biomedical Applications of Cerium Oxide Nanoparticles. Environ Sci Nano 2:33-53
Cai, Xue; Yodoi, Junji; Seal, Sudipta et al. (2014) Nanoceria and thioredoxin regulate a common antioxidative gene network in tubby mice. Adv Exp Med Biol 801:829-36
Cai, Xue; Seal, Sudipta; McGinnis, James F (2014) Sustained inhibition of neovascularization in vldlr-/- mice following intravitreal injection of cerium oxide nanoparticles and the role of the ASK1-P38/JNK-NF-?B pathway. Biomaterials 35:249-58
Wong, Lily L; Hirst, Suzanne M; Pye, Quentin N et al. (2013) Catalytic nanoceria are preferentially retained in the rat retina and are not cytotoxic after intravitreal injection. PLoS One 8:e58431
Kyosseva, Svetlana V; Chen, Lijuan; Seal, Sudipta et al. (2013) Nanoceria inhibit expression of genes associated with inflammation and angiogenesis in the retina of Vldlr null mice. Exp Eye Res 116:63-74
Das, Soumen; Dowding, Janet M; Klump, Kathryn E et al. (2013) Cerium oxide nanoparticles: applications and prospects in nanomedicine. Nanomedicine (Lond) 8:1483-508
Cai, Xue; Sezate, Steven A; Seal, Sudipta et al. (2012) Sustained protection against photoreceptor degeneration in tubby mice by intravitreal injection of nanoceria. Biomaterials 33:8771-81

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