Pediatric retinal detachment is a leading cause of childhood blindness in developed countries. One of the common characteristics of inherited or acquired pediatric retinal detachments is the subretinal exudation of fluid, hemorrhage and lipid, causing separation of photoreceptors from the retinal pigment epithelium (RPE) and the death of photoreceptors. However, a significant portion of children re-gain limited vision once the retina re-attaches after the resolution of subretinal exudate, which indicates that some photoreceptors are able to survive the prolonged separation from the RPE. The primary aim of this research study is to characterize the neuroprotective pathways regulating the survival mechanisms to keep photoreceptors alive despite persistent ischemia and toxicity. The long-term goal of this work is to design therapeutic agents to enhance intrinsic neuroprotective pathways to improve visual recovery. The over-arching hypothesis we are using to formulate this research proposal is that activation of retinal neuroprotective pathways inhibit photoreceptor apoptosis and prevent outer retinal degeneration during periods of pediatric exudative retinal detachment. We are proposing to identify these neuroprotective pathways using clinical samples from pediatric patients with exudative retinal detachment and characterizing them in a rodent model of exudative retinal detachment. We will test our central hypothesis with three specific aims: 1) Targeted analysis of retinal neuroprotective factors in pediatric exudative retinal detachment; 2) Functional analysis of neuroprotective proteins in rodent subretinal hemorrhage, an animal model for exudative retinal detachment; 3) Identification of novel neuroprotective and apoptotic pathways activated in pediatric exudative retinal detachment using human proteomics. My academic appointment as a pediatric retina specialist provides the ideal environment to translate clinical problems into research questions and transform research findings into clinical tools. As a faculty member at the University of Michigan, my clinical duties will include treating children with pediatric retinal disorders and my research program will explore the neuroprotective networks that regulate photoreceptor survival in diseased retinas. My ultimate goal as a physician-scientist is to develop new therapeutic agents to improve vision in children with retinal diseases. The Department of Ophthalmology and Visual Sciences and the University of Michigan has a world-class faculty and facilities. I will benefit from thoughtful hands-on mentoring by experienced scientists and clinicians who are deeply committed to my success. This training will be further enhanced by my interaction with the leading experts in the field of pediatric retina from Oakland University and Beaumont Eye Institute. Some of the proposed experiments involve the use of proteomics and bioinformatics. The new expertise gained in these areas through hands-on biotechnology training courses and didactic sessions will allow me to apply the power of proteomics to pediatric retinal diseases.

Public Health Relevance

Pediatric retinal detachment secondary to Retinopathy of Prematurity and other acquired or inherited retinal disorders is a leading cause of childhood blindness in developed countries. Declined visual function and blindness in children following retinal detachment represent important public health challenges, requiring life-long vision services, loss of productivity for patients and care-givers, and reduced quality of life. This projct uses a multifaceted approach utilizing both an animal model and human samples to identify neuroprotective pathways that will form a platform to develop novel therapeutic agents to prevent vision loss in pediatric retinal disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08EY023982-03
Application #
8997096
Study Section
Special Emphasis Panel ()
Program Officer
Agarwal, Neeraj
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
3
Fiscal Year
2016
Total Cost
$184,950
Indirect Cost
$13,700
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Smith, Andrew; Pawar, Mercy; Van Dort, Marcian E et al. (2018) Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors. J Ocul Pharmacol Ther 34:477-485
Dedania, Vaidehi S; Ozgonul, Cem; Zacks, David N et al. (2018) NOVEL CLASSIFICATION SYSTEM FOR COMBINED HAMARTOMA OF THE RETINA AND RETINAL PIGMENT EPITHELIUM. Retina 38:12-19
Sengupta, S; Sindal, M D; Besirli, C G et al. (2018) Screening for vision-threatening diabetic retinopathy in South India: comparing portable non-mydriatic and standard fundus cameras and clinical exam. Eye (Lond) 32:375-383
Pawar, Mercy; Busov, Boris; Chandrasekhar, Aaruran et al. (2017) FAS apoptotic inhibitory molecule 2 is a stress-induced intrinsic neuroprotective factor in the retina. Cell Death Differ 24:1799-1810
Todorich, Bozho; Thanos, Aristomenis; Yonekawa, Yoshihiro et al. (2017) Correspondence. Retina 37:e52-e54
Ozgonul, Cem; Besirli, Cagri Giray (2017) Recent Developments in the Diagnosis and Treatment of Ocular Toxoplasmosis. Ophthalmic Res 57:1-12
Padhi, Tapas Ranjan; Das, Sujata; Sharma, Savitri et al. (2017) Ocular parasitoses: A comprehensive review. Surv Ophthalmol 62:161-189
Davila, Jose R; Sengupta, Sabyasachi S; Niziol, Leslie M et al. (2017) Predictors of Photographic Quality with a Handheld Nonmydriatic Fundus Camera Used for Screening of Vision-Threatening Diabetic Retinopathy. Ophthalmologica 238:89-99
Wubben, Thomas J; Pawar, Mercy; Smith, Andrew et al. (2017) Photoreceptor metabolic reprogramming provides survival advantage in acute stress while causing chronic degeneration. Sci Rep 7:17863
Van Dort, Marcian E; Galbán, Stefanie; Nino, Charles A et al. (2017) Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168). ACS Med Chem Lett 8:808-813

Showing the most recent 10 out of 18 publications