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.
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.
|Chinskey, Nicholas D; Besirli, Cagri G; Zacks, David N (2014) Retinal cell death and current strategies in retinal neuroprotection. Curr Opin Ophthalmol 25:228-33|