Faculty

Joshua L. Dunaief, MD, PhD

faculty photo
Adele Niessen Professor of Ophthalmology
Department: Ophthalmology

Contact information
305B Stellar Chance
422 Curie Blvd.
Philadelphia, PA 19104-6100
Office: 215-898-5235
Education:
B.A. (Biology)
Harvard University (magna cum laude), 1987.
PhD (Microbiology)
Columbia University, 1994.
MD
Columbia University, 1996.
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Description of Research Expertise

Research Interests
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.

Rotation Projects
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.

Lab personnel:
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

Selected Publications

Liu Y, Bell BA, Song Y, Zhang K, Anderson B, Axelsen PH, Bohannan W, Agbaga MP, Park HG, James G, Brenna JT, Schmidt K, Dunaief JL, Shchepinov MS.: Deuterated docosahexaenoic acid protects against oxidative stress and geographic atrophy-like retinal degeneration in a mouse model with iron overload. Aging Cell 2022.

Sterling JK, Kam TI, Guttha S, Park H, Baumann B, Mehrabani-Tabari AA, Schultz H, Anderson B, Alnemri A, Chou SC, Troncoso JC, Dawson VL, Dawson TM, Dunaief JL.: Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein. Cell Rep 38: 110358, Feb 2022.

Zhang KR, Jankowski CSR, Marshall R, Nair R, Más Gómez N, Alnemri A, Liu Y, Erler E, Ferrante J, Song Y, Bell BA, Baumann BH, Sterling J, Anderson B, Foshe S, Roof J, Fazelinia H, Spruce LA, Chuang JZ, Sung CH, Dhingra A, Boesze-Battaglia K, Chavali VRM, Rabinowitz JD, Mitchell CH, Dunaief JL.: Oxidative stress induces lysosomal membrane permeabilization and ceramide accumulation in retinal pigment epithelial cells. Dis Model Mech 16: dmm050066, Jul 2023.

Zhang KR, Baumann B, Song Y, Sterling J, Erler EA, Guttha S, Kozmik Z, Dunaief JL.: Conditional knockout of hephaestin in the neural retina disrupts retinal iron homeostasis. Exp Eye Res 2022.

Dunaief JL.: Heavy lipids protect against heavy metals. Aging (Albany NY) 14: 4933-4934, Jun 2022.

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, Jun 2015.

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, Dec 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, May 2015.

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, Sep 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, Oct 7 1994.

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Last updated: 06/17/2024
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