Uveitis is an important cause of vision loss ranking fifth among causes of blindness in the United States. The inflammation that occurs in uveitis leads to ocular damage including glaucoma, macular edema, cataract, epiretinal membranes, and persistent media opacity. Treatments for uveitis are suboptimal;most uveitis is treated with corticosteroids, which are potent, non-specific agents that have high rates of serious ocular and systemic complications. This work aims to understand the mechanisms of autoinflammatory uveitis in the AIFU mouse model. My goal is to gain insights into the roles the innate immune system plays in ocular inflammation in order to develop novel therapeutic approaches that could prevent vision loss and blindness in patients with uveitis. Our core hypothesis is that the AIFU model serves as an animal model of autoinflammatory human uveitis with mixed innate and adaptive immune features. I propose to port the AIFU model from rats to mice to access the genetic tools available in this animal model, and to develop a novel real time reporter system to detect and monitor ocular inflammation in vivo. Using mouse genetic and immunologic assays, I will identify the contribution of the innate and adaptive immune systems to this model of autoinflammatory uveitis, and determine the role of the Mueller glia in the ocular inflammatory response.
Three specific aims are proposed to address the central hypothesis: 1) Generate the AIFU mouse model including a real time ocular inflammation reporter system. 2) Determine the role of the Mueller glia in AIFU inflammation. 3) Determine the contribution of the innate and adaptive immune response to AIFU. As an academic ophthalmologist practicing in the field of uveitis, I have both a clinical and research interest in understanding the mechanisms of ocular inflammation. As a fellow and then faculty member at the University of Washington, my clinical specialty will be treating patients with uveitis and my research program will study ocular inflammation with a focus on the innate immune system. The Department of Ophthalmology and the University of Washington Eye Institute has a world-class faculty and facilities that will help me to fully develop as a clinician-scientist. As my career develops, I will benefit from close mentoring by experienced scientists and clinicians who are deeply committed to my success.

Public Health Relevance

This project seeks to understand the roles of the innate and adaptive immune system in a new mouse model of autoinflammatory uveitis (AIFU). Uncontrolled inflammation in patients with uveitis leads to severe visual loss and blindness. As uveitis is the second leading cause of blindness in the working age population, this represents an important public health concern. Current treatments including corticosteroids and immunomodulators are non-specific, and have high rates of complications, which can sometimes be life- threatening. This mouse model will help develop a better understanding of the role of the innate immune system in ocular inflammation and allow for testing of new treatments targeting both the innate and adaptive immune system in the eye. Due to their molecular specificity, such treatments may provide safer and more effective therapies for uveitis than steroids or currently available immunomodulators.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08EY023998-01
Application #
8618805
Study Section
Special Emphasis Panel (ZEY1-VSN (02))
Program Officer
Agarwal, Neeraj
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$221,400
Indirect Cost
$16,400
Name
University of Washington
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Pakzad-Vaezi, Kaivon; Khaksari, Kosar; Chu, Zhongdi et al. (2018) Swept-Source OCT Angiography of Serpiginous Choroiditis. Ophthalmol Retina 2:712-719
Choi, Woo J; Pepple, Kathryn L; Wang, Ruikang K (2018) Automated three-dimensional cell counting method for grading uveitis of rodent eye in vivo with optical coherence tomography. J Biophotonics 11:e201800140
Pepple, Kathryn L; Chu, Zhongdi; Weinstein, Jessica et al. (2018) Use of En Face Swept-Source Optical Coherence Tomography Angiography in Identifying Choroidal Flow Voids in 3 Patients With Birdshot Chorioretinopathy. JAMA Ophthalmol 136:1288-1292
Pepple, Kathryn L; Nguyen, Macklin H; Pakzad-Vaezi, Kaivon et al. (2018) RESPONSE OF INFLAMMATORY CYSTOID MACULAR EDEMA TO TREATMENT USING ORAL ACETAZOLAMIDE. Retina :
Bajema, Kristina L; Pakzad-Vaezi, Kaivon; Hawn, Thomas et al. (2017) Tuberculous uveitis: association between anti-tuberculous therapy and clinical response in a non-endemic country. J Ophthalmic Inflamm Infect 7:19
Gutowski, Michal B; Wilson, Leslie; Van Gelder, Russell N et al. (2017) In Vivo Bioluminescence Imaging for Longitudinal Monitoring of Inflammation in Animal Models of Uveitis. Invest Ophthalmol Vis Sci 58:1521-1528
Chu, Zhongdi; Chen, Chieh-Li; Zhang, Qinqin et al. (2017) Complex signal-based optical coherence tomography angiography enables in vivo visualization of choriocapillaris in human choroid. J Biomed Opt 22:1-10
Pakzad-Vaezi, Kaivon; Pepple, Kathryn L (2017) Tubulointerstitial nephritis and uveitis. Curr Opin Ophthalmol 28:629-635
Pepple, Kathryn L; Choi, Woo June; Wilson, Leslie et al. (2016) Quantitative Assessment of Anterior Segment Inflammation in a Rat Model of Uveitis Using Spectral-Domain Optical Coherence Tomography. Invest Ophthalmol Vis Sci 57:3567-75
Kim, Alice Y; Rodger, Damien C; Shahidzadeh, Anoush et al. (2016) Quantifying Retinal Microvascular Changes in Uveitis Using Spectral-Domain Optical Coherence Tomography Angiography. Am J Ophthalmol 171:101-112

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