Description of Research Expertise:
Mechanisms and therapeutics for age-related retinal neurodegeneration
Key words: Macular degeneration, oxidative stress, iron transport, apoptosis, retina, aging, inflammation, transcriptomics
Description of Research
Age related macular degeneration (AMD) is the most common cause of irreversible blindness, yet its pathogenesis is poorly understood. Evidence suggests that cumulative oxidative damage contributes to AMD and aging in general. The Dunaief lab has found that AMD retinas have iron overload, which can cause oxidative stress. Increased understanding of retinal iron homeostasis may lead to treatments for AMD. To investigate the mechanisms of retinal iron regulation, the lab uses conditional knockout mouse models, human retinal tissue, and retinal cell tissue culture. A mouse line deficient in the iron transporting ferroxidases ceruloplasmin and hephaestin develops age-dependent retinal iron overload and retinal degeneration with features of AMD (Hahn et al., PNAS, 2004). Recent research in the lab indicates that inflammation promotes cellular iron overload in a vicious cycle leading to cell death. Our current focus is on the mechanisms of retinal iron homeostasis and development of therapeutics to protect the retina.
1)Study mechanisms of retinal iron regulation by performing histology and immunofluorescence on retinal sections from conditional knockout mice. You will learn retinal anatomy and the techniques of ocular microdissection, cryosectioning, plastic sectioning and fluorescence microscopy.
2)In retinal cell culture, study the effects of inflammatory mediators on retinal iron transporters. You will learn tissue culture, qPCR, Western analysis, and cell death assays.
3) Use FACS to isolate single retinal cell types and determine the effects of iron transporter knockouts on their transcriptome.
Delu Song, Research Associate
Ying Song, Research Specialist
Bailey Baumann, VMD/PhD Student
Edward Linton, UPenn Medical Student
Rupak Bhuyan, UPenn Medical Student
Danielle Minichino, CAMB Rotating Student
Shounan Qi, Visiting Scholar
Jacob Sterling, UPenn Undergraduate
Samy Guttha, Drexel Undergraduate
Theurl M, Song D, Clark E, Sterling J, Grieco S, Altamura S, Galy B, Hentze M, Muckenthaler MU, Dunaief JL: Mice with hepcidin-resistant ferroportin accumulate iron in the retina. FASEB J 30 (2): 813-23,2016.
Song D, Song J, Wang C, Li Y, Dunaief JL: Berberine protects againstlight-induced photoreceptor degeneration in the mouse retina. Exp Eye Res 145 : 1-9,2016.
Bhoiwala DL, Dunaief JL: Retinal abnormalities in β-thalassemia major. Surv Ophthalmol 61 (1): 33-50,2016.
Zhao L, Hadziahmetovic M, Wang C, Xu X, Song Y, Jinnah HA, Wodzinska J, Iacovelli J, Wolkow N, Krajacic P, Weissberger AC, Connelly J, Spino M, Lee MK, Connor J, Giasson B, Harris ZL, Dunaief JL: Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem 135 (5): 958-74,2015.
Bhoiwala Devang L, Song Ying, Cwanger Alyssa, Clark Esther, Zhao Liang-liang, Wang Chenguang, Li Yafeng, Song Delu, Dunaief Joshua L: CD1 Mouse Retina Is Shielded From Iron Overload Caused by a High Iron Diet. Investigative ophthalmology & visual science 56 (9): 5344-52,2015.
Gelfand Bradley D, Wright Charles B, Kim Younghee, Yasuma Tetsuhiro, Yasuma Reo, Li Shengjian, Fowler Benjamin J, Bastos-Carvalho Ana, Kerur Nagaraj, Uittenbogaard Annette, Han Youn Seon, Lou Dingyuan, Kleinman Mark E, McDonald W Hayes, Núñez Gabriel, Georgel Philippe, Dunaief Joshua L, Ambati Jayakrishna: Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome. Cell reports 11 (11): 1686-93,2015.
Li Y, Song D, Song Y, Zhao L, Wolkow N, Tobias JW, Song W, Dunaief JL: Iron-induced Local Complement Component 3 (C3) Up-regulation via Non-Canonical TGF-β Signaling in the Retinal Pigment Epithelium. Journal Biol Chem 290 (19): 11918-34,2015.
Guo LY, Alekseev O, Li Y, Song Y, Dunaief JL: Iron Increases APP Translation and Amyloid-Beta Production in the Retina Exp Eye Res 129 : 31-7,2014.
Hahn, Paul. Qian, Ying. Dentchev, Tzvete. Chen, Lin. Beard, John. Harris, Zena Leah. Dunaief, Joshua L.: Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 101 (38): 13850-5,2004.
Dunaief, J L. Strober, B E. Guha, S. Khavari, P A. Alin, K. Luban, J. Begemann, M. Crabtree, G R. Goff, S P.: The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79 (1): 119-30,1994.
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