CAROT

Welcome to the Ocular Genetics Laboratory of Joan O’Brien, MD at the Scheie Eye Institute. Our research team has extensive experience studying the genetics of retinoblastoma, uveal melanoma, and glaucoma.  Our laboratory facilities include next-generation sequencing and high-throughput, automated Sanger sequencing capabilities, allowing us to conduct high-impact translational genetics research. We have specific expertise in molecular sub-classification and endophenotyping of ocular disease. Previously, our team identified numerous variants in the retinoblastoma gene, allowing us to offer genetic testing to retinoblastoma patients through the eyeGENE™ initiative. Today, we are conducting a large-scale genetic analysis on African Americans with primary open-angle glaucoma. Research also in conjunction with Chavali Lab

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Molecular, Genetic, and Functional Genomic approaches to study Age-related Macular Degeneration and Primary Open-Angle Glaucoma.

Research in the Chavali lab is aimed at elucidating the pathobiology of the AMD and POAG so that treatments can be developed for these blinding diseases. Our laboratory adapts the “disease in a dish” and relevant in vivo models to study these diseases. The lab applies multi-disciplinary approaches to studying retinal pathology in Age-related Macular Degeneration (AMD) and Primary Open-Angle Glaucoma (POAG). 

The lab is investigating mechanisms leading to AMD by i) investigating the role of non-coding RNA associated with AMD, ii) characterizing the lipid pathways in RPE that are responsible for the biogenesis of soft drusen, or sub-retinal drusen deposits in AMD using in vitro systems and transgenic mouse models, and, iii) Understanding the functions of AMD associated genes using CRISPR/Cas9 gene editing methodologies in primary and human induced pluripotent stem cell- derived RPE cultures and also using animal model studies.

Our lab is also involved in the understanding the molecular pathobiology of Primary Open-Angle Glaucoma (POAG) in African Americans in collaboration with Dr. Joan O'Brien's lab. The molecular characterization studies in POAG include in vitro functional characterization of POAG associated variants, transcriptome profiling of normal and POAG African American patient's iPSC-RGCs to understand POAG-associated differentially expressed genes and noncoding RNA, and investigating the role of mitochondrial haplogroup association with POAG.

To drive translation approaches to these blinding diseases, our lab has established in vitro models to study the developmental and blinding disorders using induced pluripotent stem cells (iPSCs), to study how dysregulated downstream pathways are related to clinical manifestations. Our lab is currently working with the CAROT center to develop and standardize methods to differentiate patient-specific pluripotent stem cells (with and without pathogenic mutations) direct them towards development of retinal organoids and retinal cell types (RPE, RPCs and RGC) using in vitro differentiation assays. Our goal is to identify mechanisms that may lead to a better understanding of AMD and/or POAG disease progression and new targets for therapeutic interventions.

Open Positions:
Please contact Dr. Chavali (vchavali@pennmedicine.upenn.edu) to inquire about research opportunities in our lab.

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As gene and cell therapies begin to address a spectrum of currently incurable or virtually untreatable diseases, readily controllable (ligand-dependent) regulatory systems are an attractive approach for dosing therapeutic proteins. A key obstacle that needs to be overcome is the ability to effectively regulate the level of transgene expression. A primary focus of the lab is to create novel regulatory modules that have the potential to modulate, stop, or resume transgene expression in response to disease evolution. The full application of the system stands to transform gene and cell-based therapy and will impact a diversity of fields, including infectious disease, autoimmune disorders, metabolic disease, cardiovascular disease, and cancer. More specifically, we are focusing on therapeutic antivascular protein regulation in the retina in collaboration with Dr. Bennett’s Lab, as well as chimeric antigen receptor regulation with Dr. Milone’s Lab.

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Our research is focused on exploration of early mechanisms in the pathogenesis of age-related macular degeneration. We aim to study the interplay between the cells in the neurosensory retina with the goal to identify new clinical biomarker for detection of early AMD.The purpose not only is to understand the disease better, but also to determine possible clinical or imaging biomarkers of progression that can be used in the clinical trials. We also exploring these events at the molecular level to identify new potential treatment targets for early and in general dry AMD.

Dr. Katayoon Ebrahimi

Dr. Ebrahimi is a medical retina, ocular pathology and ocular oncologist. She has trained in Moorfields eye Institute, Johns hopkins and UCSF and Duke University. Her research is focused on age-related macular degeneration. Dr Ebrahimi identified CD46 and CD59 as important retinal pigment epithelium (RPE) cell membrane complement regulators, which are decreased in AMD.

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Currently, the treatment of glaucoma, despite increased prevalence of the disease and recent advancements in genetics and cell biology, has not changed in over 180 years. A mainstay of treatment is lowering the IOP using topical medications, laser therapy, or surgery to increase aqueous outflow within or outside of the eye.bThese current treatment modalities do not address the overwhelming complication of compliance that hampers successful treatment of this disease. Dr. Ross’s laboratory investigates in vitro and in vivo models to develop neuroprotection strategies that could be used to treat glaucoma. Read More...

Ahmara Gibbons Ross, MD, PhD

Dr. Ross is an Assistant Professor of Ophthalmology at the Scheie Eye Institute and Neurology at the Hospital of the University of Pennsylvania (HUP) and a member of the Glaucoma and Neuro-Ophthalmology Service. She received her BA degree in Chemistry at Bryn Mawr College and earned both an M.F. and a Ph.D. in molecular pharmacology and structural biology at Thomas Jefferson University. Dr. Ross’s studies focus on retinal ganglion cell (RGC) damage and mechanisms of cell death that occur during optic nerve damage from stretch and elevated intraocular pressure conditions that occur in glaucoma.   

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Our laboratory is interested in the development of gene-based strategies for the treatment of bleeding and thrombotic diseases. In a collaborative effort, we and others have carried out early-phase clinical studies on adeno-associated viral (AAV) vectors for the treatment of severe hemophilia B (factor IX deficiency). Current projects are focused on translational research studies on the efficacy and safety of intravascular delivery of AAV vectors to skeletal muscle or liver of dogs and mice with severe hemophilia. We are also identifying biological factors that modulate AAV vectors transduction and the risk of inadvertent germline transmission in animal models.

Blockage of blood vessels causes many serious human diseases, including myocardial infarct, ischemic strokes, and venous thrombosis. They contribute to the mortality and morbidity of septic shock, chronic inflammatory injury, and vascular complications of systemic diseases. The protein C anticoagulant pathway plays a major role in the interface between coagulation and inflammatory processes. Venous thrombosis is most commonly the result of defects in the proteins that participate in the protein C anticoagulant pathway. Activated Protein C (APC) mediates anticoagulant effects and signals cellular responses that are anti-inflammatory in nature. The current notion that occlusive vascular diseases such as atherosclerosis are forms of systemic diseases in which underlying inflammatory and thrombotic processes play a critical role led us to postulate that APC could offer an alternative therapeutic option. Ongoing studies are aimed at elucidating in vivo functions of APC in a series of animal models for thrombotic and/or inflammatory diseases. Read more...

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Most of the projects in the laboratory trace back to an underlying focus on heritable and acquired diseases affecting muscle. A recent spin-off illustrates some of the excitement and unpredictability of basic research. 

As the central force-generating protein of all types of muscle, myosin can be viewed as the raison d'être for the supporting molecular machinery of muscle. An understanding of this protein, its evolutionary constraints, and its interaction with other key components of the contractile apparatus and cytoskeletal network is essential to the study of muscle disease. We have studied all of the human genes for conventional muscle myosins with the surprise finding that one of them has been mutated in a recent direct human ancestor. The temporal correlation of this mutation with the emergence of the genus Homo has provided fuel for a wide range of collaborative projects in integrative biology. Read more....

Rotation Projects 
1. Gene Transfer for Duchenne Muscular Dystrophy 
2. Molecular Evolution of Myosin Motors 
3. Pathophysiology of Skeletal and Cardiomyopathy 
4. Mechanisms of Morphological Change During Speciation

Recent Publications 

• Nature Medicine
• Medical Press
• Philadelphia Inquirer 

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Research in Dr. Shindler’s lab examines mechanisms of neuronal damage and neuroprotection in optic nerve diseases, with a specific focus on retinal ganglion cell damage during optic neuritis, an inflammatory disease of the optic nerve which commonly affects patients with multiple sclerosis. Potential neuroprotective therapies to prevent damage to the optic nerve cells and permanent visual loss are being evaluated in experimental models to identify novel ways to treat optic neuritis, using pharmacologic, gene therapy and cell biologic strategies. In addition, any therapies that are developed may have broader application for other neurologic deficits induced by multiple sclerosis, and other causes of optic neuropathy.

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