Joshua Dunaief
University of Pennsylvania, PA·Medicine & Clinical Research
Vision depends on a thin, highly active layer of tissue at the back of the eye, and that tissue is unusually vulnerable to chemical damage. Oxidative stress, the harm done by reactive oxygen molecules, and the metal iron that helps generate them are central threads in both projects.
- Fields
Medicine & Clinical Research
Biochemistry
Neuroscience
- Topics
age-related macular degeneration
geographic atrophy
retinal pigment epithelium
- Grants
- 2 known grants, through Apr 2028
What they work on
- Develop two new mouse models of geographic atrophy driven by oxidative stress in the retinal pigment epithelium: mice with RPE-specific knockout of glutathione peroxidase 4 and mice given low-dose sodium iodate.
- Test whether oral deuterated docosahexaenoic acid (D-DHA), an oxidation-resistant form of a retinal fat, prevents atrophy from forming and expanding in these models, tracked with in vivo imaging (cSLO and OCT) and electroretinography.
- Characterize retinal degeneration after euthanasia using mass spectrometry, histology, immunohistochemistry and qPCR to link lipid oxidation to tissue damage and gene expression changes.
- Test the hypothesis that the ferroxidases ceruloplasmin and hephaestin, rather than the iron exporter ferroportin, keep retinal iron in its ferric form, using AAV-mediated ceruloplasmin gene therapy in mice lacking ferroportin.
- Determine whether oxidation-resistant D-DHA protects the retina from reactive oxygen species generated by ferrous iron, addressing iron toxicity seen in AMD and aceruloplasminemia.
More about the research
Iron is needed for normal retinal function but turns toxic when poorly controlled, and oxidation of a retinal fat called docosahexaenoic acid (DHA) has been implicated in age-related macular degeneration (AMD), a leading cause of central vision loss. Both projects work in mice and both test the same candidate drug: an oxidation-resistant form of DHA in which some hydrogen atoms are replaced by the heavier isotope deuterium (D-DHA), given by mouth.
Why it matters
Age-related macular degeneration destroys central vision and current treatments are limited, especially for the advanced dry form. Iron toxicity also threatens sight after eye injuries with metal fragments, after bleeding in the eye, and in aceruloplasminemia, glaucoma, diabetic retinopathy and retinitis pigmentosa. New mouse models of geographic atrophy plus tests of an oral antioxidant and of ceruloplasmin gene therapy could identify treatments and clarify which damage mechanisms to target.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Katelyn Swindle-Reilly
Ohio State University, OH·Biomedical Engineering
Synthesize and characterize an investigational anti-inflammatory drug and load it into ROS-responsive polydopamine nanoparticles that release more drug under oxidative stress.
Jason Miller
University of Michigan, MI·Medicine & Clinical Research·Early-career
Determine the composition of lipid droplets, small fat-storage compartments, in human retinal pigment epithelium (RPE) cultures fed different lipid loads, using mass spectrometry.
Jianhai Du
West Virginia University, WV·Biochemistry
Trace how retinal pigment epithelium cells use the amino acid proline as fuel alongside glucose, using tracer methods and mass spectrometry.
The school
University of Pennsylvania: 90 labs on PI Pages, $2.2B a year on research, 750 research doctorates a year.
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