Eye / Vision
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21624
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Browsing Eye / Vision by Author "Chavala, Sai"
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Item Restoration of vision by chemically reprogrammed photoreceptors(2019-03-05) Kaya, Koray; Fan, Yan; Sumien, Nathalie; Shetty, Ritu; wei, Zhang; Davis, Delaney; Thomas Mock, Thomas; Batabyal, Subrata; Ni, Aiguo; Mohanty, Samarendra; Han, Zongchao; Farjo, Rafal; Forster, Michael; Swaroop, Anand; Chavala, Sai; Mahato, BirajPurpose: Many retinopathies such as Retinitis Pigmentosa, Stargardt disease, Cone-rod dystrophy, Achromatopsia, Chroideremia and Labor congenital Amaurosis (LCA) comprise a wide range of genetically and phenotypically heterogeneous conditions that share common progressive loss of photoreceptor function accompanied by irreversible vision loss. Majority of the patients affected by these diseases present with uncorrectable decreased visual acuity during their childhood years, which most often progress to legal blindness. Strategy to restore vision with photoreceptor like replacement cell has the advantage of being applied to these patients, regardless of their genetic dysfunction or stage of disease. Currently no FDA approved treatments are available to treat these disorders. We have discovered a chemical engineering method that can convert fibroblasts to chemically induced photoreceptors (CiPCs) with their ability to restore vision in retinal degeneration mouse model. Methods: A combination of small molecule (5C) was used to convert fibroblasts to CiPCs. Gene expression of CiPCs was analyzed by RNA sequencing, RT-PCR and immunofluorescence. Light responsiveness of CiPCs was tested by single cell patch clamp recording upon stimulation with light. In vivo CiPC function was examined by pupil analysis, light aversion test, visual acuity and contrast sensitivity measurement after injecting them into retinal degeneration mouse model. Results: We have identified a set of five small molecules (5C) that induces mouse embryonic fibroblasts (MEFs) and human adult dermal fibroblasts (HADF) into CiPCs both rods and cones, without the use of pluripotent cells or viral transcription factors in less than two weeks time. Detailed analyses have been performed in mouse cells, but in brief, these cells express transcript and proteins consistent with youthful photoreceptors (postnatal day 5). In vitro functional analysis indicated that CiPCs are light responsive. Moreover, when mouse ciPCs are injected into the subretinal space of retinal degeneration mutant mice (rd1), in some mice (approximately 50%) we observed cell survival for several months (more than 120 days), restored light-dark preference/discrimination, improved scotopic-Optomotry testing, fleeting but partial ERG recovery, and restoration of pupillary reflexes. Conclusions: Based upon these observations we demonstrate restoration of visual functions by CiPCs that carry extraordinary translational potential for millions of visually impaired patients worldwide.Item The Endothelin Receptor Antagonist Macitentan Ameliorates Endothelin-Mediated Vasoconstriction and Promotes Neuroprotection of Retinal Ganglion Cells in Rats.(2019-03-05) Krishnamoorthy, Vignesh; wei, Zhang; Kodati, Bindu; Chavala, Sai; Krishnamoorthy, Raghu; Stankowska, Dorota; Harris, PaytonThe Endothelin Receptor Antagonist Macitentan Ameliorates Endothelin-Mediated Vasoconstriction and Promotes Neuroprotection of Retinal Ganglion Cells in Rats. Payton Harris Vignesh Krishnamoorthy Wei Zhang Bindu Kodati Sai Chavala Raghu Krishnamoorthy Dorota L. Stankowska 1. Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth TX 76107 2. Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth TX 76107 Purpose: To determine if dietary administration of the dual ETA/ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) following endothelin-1 mediated vasoconstriction in Brown Norway rats. Methods: Adult male and female Brown Norway rats were either untreated or treated with macitentan (5 mg/kg body weight) once a day for 3 days followed by intravitreal injection of either 4 µl of 500 mM ET-1 or vehicle in one eye. Imaging of the retinal vasculature using fluorescein angiography was carried out a various time points including 2, 5, 10 and 20 minutes. Following the imaging of the vasculature, treatment of rats was continued for 1 week with either macitentan (5 mg/kg/body weight) in dietary gels or untreated control gels. After euthanizing the rats, retinal flat mounts from the rats were prepared, immunostained for RGC marker Brn3a, imaged and surviving RGCs were counted in a masked manner. Results: Vasoconstrictive effects following intravitreal ET-1 injection were greatly reduced in rats administered with macitentan in the diet prior to the ET-1 administration. ET-1 intravitreal injection produced a 45% loss of RGCs which was significantly reduced in macitentan-treated rats and RGC counts were similar to that observed in control retinas. Conclusions: The endothelin receptor antagonist, macitentan, has neuroprotective effects in retinas of Brown Norway rats that occurs through different mechanisms, including, enhancement of RGC survival and reduction ET-1 mediated vasoconstriction preventing ischemia.