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Drusen develop as yellow deposits under the retina and are considered to be hallmarks of age-related macular degeneration; this proposal utilizes cutting-edge recombinant antibody technologies to develop novel anti-drusen “nanobody” molecules that have the potential to serve as direct therapeutics and/or drug discovery tools for AMD. Nanobodies can be selected, engineered, and manipulated as genes, then delivered as either genes or proteins to modulate drusen. Since similar reagents are already in human clinical trials for other abnormal protein diseases, translation to clinical ophthalmology is highly feasible.

New biomarker detection techniques could improve early diagnosis of age-related macular degeneration (AMD), which is important for early treatment to delay or reduce disease severity. Dr. Wei Li and colleagues will systematically identify the levels and identities of various “anti-retinal autoantibodies,” particular types of biomarkers that are found in AMD patients’ blood. These special types of self-reacting antibodies previously have been detected in AMD patient blood, but identifying a signature or fingerprint map of the complete autoantibody profile could potentially be used for early diagnosis of AMD.

The specific aims outlined in this proposal will provide a cell biological understanding of the role of a protein called apolipoprotein E and the regulation of cholesterol levels in the retinal pigment epithelial (RPE) tissue of the eye). We will also investigate the potential of two promising drugs, statins and PPARgamma agonists, which are currently being used to treat, respectively, atherosclerosis and diabetes. These drugs will be tested for their ability to maintain cholesterol balance in the RPE.

The function of long non-coding RNA (lncRNA) in the genome and their role in biological processes and disease is not well studied even though some lncRNA are known to be associated with neurological diseases. Dr. Chavali’s team proposes to sequence the total retina and retinal pigment epithelium (RPE) tissue transcriptome (the total collection of RNAs that are expressed within cells at that point in time) from normal and age-related macular degeneration (AMD) donor eyes. Analysis of these sequences will reveal the differentially expressed (DE) lncRNAs and messenger RNAs (mRNAs) that are relevant to AMD and expressed in the retina and RPE/choroid. The team intends to characterize the role of DE lncRNAs in AMD and understand how lncRNAs potentially influence the development of AMD. The outcome of this project will provide novel pathways to understand what is involved with the initiation and progression of AMD. Defining the expression changes of lncRNAs in AMD may lead to the development of new biomarkers and therapies.

Geographic atrophy (GA) is a form of age-related macular degeneration (AMD), and increasingly the main cause of vision loss in patients. Much of the previous research of GA has focused on individual imaging modalities, utilizing two-dimensional (2D) information alone. However, considering the 3D topology of the disease, utilizing information from all imaging modalities concomitantly could potentially yield a more precise and comprehensive depiction of GA lesions. The overall goal of this project is to develop an automated multimodal GA segmentation system to more precisely quantify GA progression over time in multimodal 2D and 3D images to facilitate the understanding of GA’s relationship to vision loss. 

We are developing an open source fully-automated software program with demonstrated high accuracy that is able to detect, segment, and analyze Neovascular AMD (NVAMD) pathology seen on optical coherence tomography and compare these data to corresponding features on other imaging modalities. We anticipate that the software tools developed in this proposal will be readily adopted by clinicians, clinical study sites, and image Reading Centers to better identify NVAMD at the earliest stages, to quantify disease progression, and to measure response to therapy.

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. More than 11 million Americans are affected by AMD, and there is relatively little in the way of effective treatment until the disease become advanced. Autophagy is a self-eating process in the cells that involves degradation of unwanted cellular components to supply the cell with energy when needed. Failure in autophagy is related to diseases. We propose to study the role of autophagy and its possible dysfunction in AMD.

Age-related macular degeneration (AMD) is characterized by the presence of drusen, abnormal extracellular deposits composed of protein and lipids that accumulate between the RPE and choroid, the layer of blood vessels providing oxygen and nutrients to the RPE. Our goal is to understand the factors contributing to the formation of drusen deposits, in order to develop a strategy to eliminate them and preserve vision in AMD patients.

Drug therapy only slows the progression of disease, but does not represent a regenerative approach to macular degeneration treatment. We will use cell regenerative techniques to produce large quantities of cone photoreceptors for transplantation directly into the retina. Cones are the cells responsible for high-resolution/color vision and are lost in disease. We will take advantage of natural biomaterials as vehicles to deliver cells to the eye, to increase their survival and improve their function after transplantation.