The specific aims of this proposal are to: 1) examine molecular mechanisms of retinal degenerative diseases using biochemical, molecular biological and physiological techniques;2) establish retinal disease models of macular degeneration in mice;and 3) use these animal models to evaluate the safety and efficacy of pharmaceutical candidates for human drug development. Our achievements in series of studies with the visual retinoid cycle related retinal degenerative murine models leaded to discover novel disease causing mechanisms and to develop molecules that are strong candidates of treatment options for patients with retinal degenerations including inherited retinal degenerations and AMD (age-related macular degeneration), which is the leading cause of irreversible blindness in elderly people in developed countries, and which affects approximately 1.6 million individuals in the US. Recent ocular medical science succeeded in develop anti-CNV (choroidal neo-vasucularization) therapy with anti-VEGF (vascular endothelial growth factor) molecules for wet type AMD with CNV growth. However wet type AMD is only limited type of retinal diseases, and no treatment is available for the vast majority of patients who have dry form of AMD and other inherited retinal degenerative diseases. The molecules that we are studying show several beneficial effects on these incurable retinal diseases, and may become a first drug for them. Genetically modified mice will be employed for our study and rigorous evaluations including mechanisms, efficacy and safety of our candidate drugs by biochemical methods such as HPLC (high pressure liquid chromatography) and mass-spectrometry, and electroretinography, and histological/histocytochemical assessment. Molecular pathogenesis of dry type AMD and inherited retinal degeneration will be also examined with the murine models. My research based on my clinical experience is providing novel and important solutions for patients with currently incurable retinal degenerative diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZEY1-VSN (08))
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Agarwal, Neeraj
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Case Western Reserve University
Schools of Medicine
United States
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Kohno, Hideo; Maeda, Tadao; Perusek, Lindsay et al. (2014) CCL3 production by microglial cells modulates disease severity in murine models of retinal degeneration. J Immunol 192:3816-27
Maeda, Akiko; Palczewska, Grazyna; Golczak, Marcin et al. (2014) Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice. Proc Natl Acad Sci U S A 111:E1428-37
Sawada, Osamu; Perusek, Lindsay; Kohno, Hideo et al. (2014) All-trans-retinal induces Bax activation via DNA damage to mediate retinal cell apoptosis. Exp Eye Res 123:27-36
Perusek, Lindsay; Maeda, Tadao (2013) Vitamin A derivatives as treatment options for retinal degenerative diseases. Nutrients 5:2646-66
Kawamura, Shiho; Gerstung, Moritz; Colozo, Alejandro T et al. (2013) Kinetic, energetic, and mechanical differences between dark-state rhodopsin and opsin. Structure 21:426-37
Chen, Yu; Sawada, Osamu; Kohno, Hideo et al. (2013) Autophagy protects the retina from light-induced degeneration. J Biol Chem 288:7506-18
Kohno, Hideo; Chen, Yu; Kevany, Brian M et al. (2013) Photoreceptor proteins initiate microglial activation via Toll-like receptor 4 in retinal degeneration mediated by all-trans-retinal. J Biol Chem 288:15326-41
Maeda, Akiko; Golczak, Marcin; Chen, Yu et al. (2012) Primary amines protect against retinal degeneration in mouse models of retinopathies. Nat Chem Biol 8:170-8
Okano, Kiichiro; Maeda, Akiko; Chen, Yu et al. (2012) Retinal cone and rod photoreceptor cells exhibit differential susceptibility to light-induced damage. J Neurochem 121:146-56
Chen, Yu; Okano, Kiichiro; Maeda, Tadao et al. (2012) Mechanism of all-trans-retinal toxicity with implications for stargardt disease and age-related macular degeneration. J Biol Chem 287:5059-69

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