Visual recovery after repair of a retinal detachment is often disappointing with more than half of treatedpatients reporting below normal visual acuity. Retinal neurons undergo dramatic structural plasticity afterdetachment including retraction of rod axons, rounding of cone terminals, and sprouting by bipolar andhorizontal cells. Some of these changes occur within hours after retinal injury in animal models. It has beensuggested that this synaptic remodeling contributes to poor visual recovery. In retinal cell cultures,activation of the RhoA-Rho kinase (ROCK) signaling cascade is primarily responsible for rod axonretraction. Thus, this application tests the hypothesis that a combined therapy of RhoA-antagonists andretinal surgery may significantly improve the visual outcome after repair of a detached retina by preventingor reducing synaptic plasticity. This hypothesis will be tested on adult pigs, whose eyes are similar to humaneyes, focusing on the following specific aims: 1) To test whether RhoA antagonists which inhibit the activityof RhoA, ROCK, or their substrates will prevent the structural synaptic changes caused by detachmentincluding rod axon retraction, rod-bipolar synaptic dissolution, cone terminal morphological change, andbipolar cell sprouting. The effect on glial cell reactivity will also be examined; 2) To determine whetherRhoA-related drugs can be applied after a detachment, a more therapeutically relevant scenario, and if so,how long after the injury; and 3) To determine if detached retinas treated with RhoA-related drugs indeedhelp visual structural and functional recovery after reattachment surgery. Morphology will be assessed byimmunohistochemistry, image analysis and confocal laser scanning and electron microscopy. Levels ofactivity and the time-course of Rho signaling will be determined by biochemical assays for multiplecomponents including RhoA activation and myosin light chain phosphorylation. Retinal function afterreattachment will be assessed by electroretinograms. Some of the drugs that will be tested (Ct-04 andfasudil) have already been approved for human use. We hope to establish the approximate dosage andmode of application to be tested in patients, if RhoA antagonists prove to be a useful adjunct to surgicalreattachment.
|Effective start/end date||2/1/12 → 1/31/18|
- National Institutes of Health (NIH)