While much is known on the causes of epiretinal membrane formation in retina diseases such as Proliferative Vitreoretinopathy (PVR) and Proliferative Diabetic Retinopathy (PDR), the progression of cell transformation into myocontractile phenotype and the machinery responsible for the contraction is less understood. The long-term goal is that when a membrane in patients with Proliferative Vitreoretinopathy or Proliferative Diabetic Retinopathy is identified we have an understanding of the contraction machinery responsible and can prescribe treatments to stop or reverse membrane contraction. The objective of this proposal is to determine the components of the contraction machinery that are essential for membrane contraction. The central hypothesis is contraction associated genes we identify during whole transcriptome sequencing of patient epiretinal membranes are components of the contraction machinery are responsible for membrane contraction and retinal detachment in patients with PVR and PDR. The rational underlying this proposal is that completion will identify key physical targets that when disabled will prevent or reverse membrane contraction. The central hypothesis will be tested by pursuing two specific aims: 1) To determine the mechanisms underlying the transformation of retinal pigment epithelium (RPE) into a contracting membrane. 2) To identify contraction-associated genes in the membranes from patients with PVR and PDR and evaluate their necessity for contraction by retinal cells in a new model of membrane contraction and a well established animal model. We will pursue these aims using an innovative combination of analytical and manipulative techniques. These include using the protocol we designed to isolate RNA from patient dissected membranes with sufficient yield and quality enabling whole transcriptome sequencing. Additionally we will use retina cell culture methods and a new model of contraction developed by this team that enables the preservation of native physiology and resembles the disease contraction phenotype. We will use these new methods in tandem with well-established techniques in molecular biology. The research proposal is significant, because the results will identify the machinery responsible for retinal membrane contraction and vision loss in PVR and PDR. From this understanding, new therapeutic approaches may be developed for rescuing patients from vision loss. The expected outcome of this work is a more complete understanding of retinal membrane formation and contraction in two devastating eye diseases, which will provide insight into other fibrotic membrane diseases of the retina. The results will have a positive impact immediately as the new knowledge gained will point to new targets for the prevention of vision loss.
The proposed research is relevant to public health because retinal detachment due to fibrotic membrane contraction leads to vision loss in millions of people worldwide every year and understanding the mechanisms responsible for membrane contraction may lead to the development of therapies to prevent future vision loss. Thus, this proposal is relevant to the part of NIH?s mission that pertains to fostering fundamental creative discoveries and innovative research strategies as a basis for ultimately protecting health.
