This grant addresses NEI research priorities to identify the genes involved in retinal degenerative diseases and study inflammatory eye disease. The eye is an immune privileged site where the molecular basis of local immunological mechanisms is poorly understood. We characterized a large family with severe intraocular inflammation and no systemic features. Based on a number of unique clinical features and its pattern of inheritance, it was named Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV). In this eye-specific, inflammatory condition, a gene defect triggers the release of intraocular cytokines that recruit inflammatory cells. Progressive disease stages lead to loss of the ERG b-wave, progressive pigmentary retinal degeneration, peripheral field loss, and eventually retinal neovascularization, retinal detachment, and glaucoma.
The specific aims of this grant are to apply advanced molecular genetic techniques to discover the causative gene for ADNIV and proteomic techniques to identify downstream cytokine signals. We will utilize a variety of genetic marker strategies to narrow the linkage interval and then test candidate genes for mutations by DNA sequencing. Eye fluid samples will be used to screen for cytokines at various stages of disease, following immunosuppression, and in comparison to other inflammatory eye diseases. Discovery of the ADNIV gene is highly significant, since there are no known genes that exclusively cause inflammatory eye disease. Moreover, the ADNIV gene and its effector cytokines may be linked to more common inflammatory eye diseases, such as diabetic retinopathy, proliferative vitreoretinopathy, and Relevance. Identifying the specific gene mutation for ADNIV will represent an important step towards understanding the basic mechanisms of eye immunology. This will allow for more targeted therapy for patients with inflammatory eye disease. The ADNIV gene will represent the first known gene with immunological effects exclusive to the eye.

Public Health Relevance

ADNIV is an inherited eye disease that shares a number of features with more common eye diseases such as diabetic retinopathy, intraocular inflammation, and retinal detachment, and retinal detachment. Discovery of the gene and downstream signals in this disease will help to understand and treat these blinding diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08EY020530-04
Application #
8607951
Study Section
Special Emphasis Panel (ZEY1-VSN (02))
Program Officer
Agarwal, Neeraj
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$227,903
Indirect Cost
$16,882
Name
University of Iowa
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Nelson, Nnamdi G; Skeie, Jessica M; Muradov, Hakim et al. (2014) CAPN5 gene silencing by short hairpin RNA interference. BMC Res Notes 7:642
Skeie, Jessica M; Mahajan, Vinit B (2014) Proteomic landscape of the human choroid-retinal pigment epithelial complex. JAMA Ophthalmol 132:1271-81
Wert, Katherine J; Skeie, Jessica M; Bassuk, Alexander G et al. (2014) Functional validation of a human CAPN5 exome variant by lentiviral transduction into mouse retina. Hum Mol Genet 23:2665-77
Chen, Jing; Ingham, Neil; Kelly, John et al. (2014) Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss. PLoS Genet 10:e1004688
Mahajan, Vinit B; Skeie, Jessica M (2014) Translational vitreous proteomics. Proteomics Clin Appl 8:204-8
Bassuk, Alexander G; Sujirakul, Tharikarn; Tsang, Stephen H et al. (2014) A novel RPGR mutation masquerading as Stargardt disease. Br J Ophthalmol 98:709-11
Skeie, Jessica M; Tsang, Stephen H; Zande, Ryan Vande et al. (2014) A biorepository for ophthalmic surgical specimens. Proteomics Clin Appl 8:209-17
Tozer, Kevin; Roller, A Brock; Chong, Lawrence P et al. (2013) Combination therapy for neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor agents. Ophthalmology 120:2029-34
White, Jacqueline K; Gerdin, Anna-Karin; Karp, Natasha A et al. (2013) Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell 154:452-64
Bakall, Benjamin; Folk, James C; Boldt, H Culver et al. (2013) Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol 156:15-22.e1