Department of Pediatrics
McPherson Eye Research Institute
University of Wisconsin
Madison, WI

BASIC RESEARCH PROJECT

Treatment and prevention of PVR and retinal detachment

Current Research Interests

Retinal detachment (RD) is a vision-threatening condition that requires surgical treatment. RD is accompanied by inflammation that can lead to proliferative vitreoretinopathy (PVR) in up to 20% of patients. Since unchecked inflammation is a driving force in PVR, removal of unhelpful cells that fuel inflammation would be an important treatment in RD patients. Dr. Sorenson’s laboratory studies Bcl-2, a protein that prevents cells from dying. Increased Bcl-2 activity can cause cells to live longer than they should, contributing to persistent inflammation, new vessel growth and scarring. The innovation of this proposal is that it investigates whether increasing the clearance of cells that enhance inflammation, by decreasing Bcl-2 activity, improves vision outcomes for PVR patients by decreasing or reversing scar formation. A better understanding of the critical role Bcl-2 plays in this process will allow us to decrease scar formation and reverse the scars that have already formed. This will be accomplished by decreasing Bcl-2 activity by gene deletion in inflammatory cells and with the FDA approved drug ABT-199, an inhibitor of Bcl-2 activity used to treat various cancers. The knowledge obtained from these studies should be translatable to PVR as well as other eye diseases in which scar formation is a major problem.

Plans for 2024

Purpose of Project: The purpose of this project is to improve vision outcomes for PVR
patients by preventing or decreasing scar formation.

Dr. Sorenson has made great progress optimizing the PVR model and staining protocol and now has a good-sized breeding colony of mice lacking Bcl-2 in mononuclear phagocytes that will be utilized to execute the experiments proposed in the grant. Mice lacking Bcl-2 in mononuclear phagocytes will be studied to delineate whether moderating the lifespan of this inflammatory subset diminishes PVR. In addition, the lab will administer ABT-199 and/or etomoxir to newly forming or established scars to modulate Bcl-2 and determine the efficacy of these treatments for PVR. Should it be determined that Bcl-2 drives inflammation and scarring during the formation of PVR, Dr. Sorenson will assess whether lack of Bcl-2’s opposing family member Bim enhances PVR. Together these studies will give us a better understanding of the importance of modulating immune cell turnover in treatment of PVR.

Specific Aims: To test the hypothesis that Bcl-2 expression and activity in
microglia and recruited myeloid cells plays an important role during retinal scar formation.

The major cell types of the retinal vasculature are endothelial cells, pericytes and astrocytes. Retinal astrocytes act as an intermediary between neural and vascular cells facilitating retinal vascular development, remodeling and maintaining normal function and neuronal integrity. Astrocytes surround maturing blood vessels, imparting barrier properties to the endothelia and facilitate revascularization following ischemia. Loss of retinal astrocytes aids retinal vascular rarefaction during the pathogenesis of retinopathy of prematurity (ROP) and diabetic retinopathy.

About 1,500 preterm infants in the United States become blind annually. Unfortunately, the main reason for the inherent sensitivity of the developing retinal vascular to changes in oxygen levels remains elusive. Preterm infants exposed to high levels of oxygen are predisposed to ROP due to attenuation of retinal vascular development and apoptotic loss of existing blood vessels. When infants return to room air the ischemic retina promotes pathologic growth of new blood vessels, which are fragile and leaky. Unfortunately intravitreal anti-VEGF enters the general circulation, leading to increased risk of systemic complications during this critical period of lung and kidney development.

Bim is a member of the Bcl-2 family of proteins, with important function in maintaining mitochondrial homeostasis and cell death. Bim not only regulates cell death but also influence the extracellular matrix (ECM) milieu, impacting cell adhesion and migration in a cell-type specific manner.

Progress in 2013

Dr. Sorenson hypothesized that enhanced astrocytic Bim expression in response to hyperoxia, facilitates retinal vascular rarefaction either locally during remodeling or on a larger scale during ROP. Her published studies demonstrate protection of the developing retinal vasculature from hyperoxia-mediated vessel obliteration, cessation of vascularization of the inner retina and ischemia-driven neovascularization in the absence of Bim.

She has found that Bim deletion in endothelial cells and/or pericytes was insufficient to prevent hyperoxia-mediated vessel obliteration. This study will test the hypothesis that Bim expression in astrocytes facilitates normal and pathologic retinal vessel remodeling. Enhancing astrocyte survival and function through decreasing Bim expression should prevent the first phase of ROP when normal blood vessels are being destroyed, preserving neuronal integrity and function.

Specific Aim: To test the hypothesis that Bim expression in astrocytes facilitates normal and pathologic retinal vessel remodeling.