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Browsing by Subject "Retinitis pigmentosa"
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Item Drug Discovery Strategies for Inherited Retinal Degenerations(MDPI, 2022-09-10) Das, Arupratan; Imanishi, Yoshikazu; Ophthalmology, School of MedicineInherited retinal degeneration is a group of blinding disorders afflicting more than 1 in 4000 worldwide. These disorders frequently cause the death of photoreceptor cells or retinal ganglion cells. In a subset of these disorders, photoreceptor cell death is a secondary consequence of retinal pigment epithelial cell dysfunction or degeneration. This manuscript reviews current efforts in identifying targets and developing small molecule-based therapies for these devastating neuronal degenerations, for which no cures exist. Photoreceptors and retinal ganglion cells are metabolically demanding owing to their unique structures and functional properties. Modulations of metabolic pathways, which are disrupted in most inherited retinal degenerations, serve as promising therapeutic strategies. In monogenic disorders, great insights were previously obtained regarding targets associated with the defective pathways, including phototransduction, visual cycle, and mitophagy. In addition to these target-based drug discoveries, we will discuss how phenotypic screening can be harnessed to discover beneficial molecules without prior knowledge of their mechanisms of action. Because of major anatomical and biological differences, it has frequently been challenging to model human inherited retinal degeneration conditions using small animals such as rodents. Recent advances in stem cell-based techniques are opening new avenues to obtain pure populations of human retinal ganglion cells and retinal organoids with photoreceptor cells. We will discuss concurrent ideas of utilizing stem-cell-based disease models for drug discovery and preclinical development.Item Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa(Cell Press, 2023) Lee, Sang Joon; Emery, Douglas; Vukmanic, Eric; Wang, Yekai; Lu, Xiaoqin; Wang, Wei; Fortuny, Enzo; James, Robert; Kaplan, Henry J.; Liu, Yongqing; Du, Jianhai; Dean, Douglas C.; Neurological Surgery, School of MedicineMost mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.Item A smartphone based method for mouse fundus imaging(Elsevier, 2021) Peng, Michael; Park, Bomina; Harikrishnan, Hemavathy; Jahan, Sultana N.; Dai, Jiannong; Rayana, Naga Pradeep; Sugali, Chenna Kesavulu; Sharma, Tasneem P.; Imanishi, Sanae; Imanishi, Yoshikazu; Corson, Timothy W.; Mao, Weiming; Ophthalmology, School of MedicineNoninvasive in vivo imaging of the mouse retina is essential for eye research. However, imaging the mouse fundus is challenging due to its small size and requires specialized equipment, maintenance, and training. These issues hinder the routine evaluation of the mouse retina. In this study, we developed a noncontact imaging system consisting of a smartphone, a 90D condensing lens, a homemade light diaphragm, a tripod, and a Bluetooth remote. With minimal training, examiners were able to capture fundus images from the mouse retina. We also found that fundus images captured using our system from wild type mice, mice with laser-induced retinal injury, and a mouse model of retinitis pigmentosa showed a quality similar to those captured using a commercial fundus camera. These images enabled us to identify normal structures and pathological changes in the mouse retina. Additionally, fluorescein angiography was possible with the smartphone system. We believe that the smartphone imaging system is low cost, simple, accessible, easy to operate, and suitable for the routine screening and examination of the mouse eye.Item Utilizing Zebrafish Visual Behaviors in Drug Screening for Retinal Degeneration(MDPI, 2017-06-02) Ganzen, Logan; Venkatraman, Prahatha; Pang, Chi Pui; Leung, Yuk Fai; Zhang, Mingzhi; Biochemistry and Molecular Biology, School of MedicineZebrafish are a popular vertebrate model in drug discovery. They produce a large number of small and rapidly-developing embryos. These embryos display rich visual-behaviors that can be used to screen drugs for treating retinal degeneration (RD). RD comprises blinding diseases such as Retinitis Pigmentosa, which affects 1 in 4000 people. This disease has no definitive cure, emphasizing an urgency to identify new drugs. In this review, we will discuss advantages, challenges, and research developments in using zebrafish behaviors to screen drugs in vivo. We will specifically discuss a visual-motor response that can potentially expedite discovery of new RD drugs.