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Browsing by Subject "Diabetic Retinopathy"
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Item Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy(Wiley Blackwell (John Wiley & Sons), 2016-02) Bhatwadekar, Ashay D.; Duan, Yaqian; Chakravarthy, Harshini; Korah, Maria; Caballero, Sergio; Busik, Julia V.; Grant, Maria B.; Department of Ophthalmology, IU School of MedicineAtaxia telangiectasia mutated (ATM) acts as a defense against a variety of bone marrow (BM) stressors. We hypothesized that ATM loss in BM-hematopoietic stem cells (HSCs) would be detrimental to both HSC function and microvascular repair while sustained ATM would be beneficial in disease models of diabetes. Chronic diabetes represents a condition associated with HSC depletion and inadequate vascular repair. Gender mismatched chimeras of ATM(-/-) on wild type background were generated and a cohort were made diabetic using streptozotocin (STZ). HSCs from the STZ-ATM(-/-) chimeras showed (a) reduced self-renewal; (b) decreased long-term repopulation; (c) depletion from the primitive endosteal niche; (d) myeloid bias; and (e) accelerated diabetic retinopathy (DR). To further test the significance of ATM in hematopoiesis and diabetes, we performed microarrays on circulating angiogenic cells, CD34(+) cells, obtained from a unique cohort of human subjects with long-standing (>40 years duration) poorly controlled diabetes that were free of DR. Pathway analysis of microarrays in these individuals revealed DNA repair and cell-cycle regulation as the top networks with marked upregulation of ATM mRNA compared with CD34(+) cells from diabetics with DR. In conclusion, our study highlights using rodent models and human subjects, the critical role of ATM in microvascular repair in DR.Item Prediction of Anti-VEGF Response in Diabetic Macular Edema After 1 Injection(2017-05) Shah, Ankoor R.; Yonekawa, Yoshihiro; Todorich, Bozho; Van Laere, Lily; Hussain, Rehan; Woodward, Maria A.; Abbey, Ashkan M.; Wolfe, Jeremy D.; Ophthalmology, School of MedicinePurpose With multiple anti-vascular endothelial growth factor and steroid therapies available for diabetic macular edema (DME), there is a need for early determination of the best treatment for a particular patient to prevent irreversible vision loss from chronic DME. In this study, we classify patients as responders or non-responders to anti-vascular endothelial growth factor (VEGF) monotherapy in the treatment of DME after a single anti-VEGF injection. Methods The study was designed as a single center, retrospective, interventional case series. We included patients who received 3 consecutive monthly injections with the same anti-VEGF agent. We excluded patients who were treated for DME in the preceding 3 months with any form of anti-VEGF therapy. Visual acuity and central retinal thickness (CRT) data were followed for one year. Receiver operating characteristic (ROC) curve analysis was performed in order to identify cutoff values for identifying responders. Results 107 eyes were reviewed, with 40 eyes of 34 patients meeting all inclusion criteria. Based on ROC curve analysis, a reduction in CRT by > 15% at 1-month, identified eyes that responded to treatment and had a >25% reduction in CRT at 3-months (sensitivity 0.75, specificity 0.92). Conclusion DME eyes that have early response to anti-VEGF treatment by reduction in CRT will have significant response to treatment by 3 months.Item Regulation of retinal inflammation by rhythmic expression of MiR-146a in diabetic retina(Association for Research in Vision and Opthalmology, 2014-06) Wang, Qi; Bozack, Svetlana N.; Yan, Yuanqing; Boulton, Michael E.; Grant, Maria B.; Busik, Julia V.; Department of Ophthalmology, IU School of MedicinePURPOSE: Chronic inflammation and dysregulation of circadian rhythmicity are involved in the pathogenesis of diabetic retinopathy. MicroRNAs (miRNAs) can regulate inflammation and circadian clock machinery. We tested the hypothesis that altered daily rhythm of miR-146a expression in diabetes contributes to retinal inflammation. METHODS: Nondiabetic and STZ-induced diabetic rats kept in 12/12 light/dark cycle were killed every 2 hours over a 72-hour period. Human retinal endothelial cells (HRECs) were synchronized with dexamethasone. Expression of miR-146a, IL-1 receptor-associated kinase 1 (IRAK1), IL-1β, VEGF and ICAM-1, as well as clock genes was examined by real-time PCR and Western blot. To modulate expression levels of miR-146a, mimics and inhibitors were used. RESULTS: Diabetes inhibited amplitude of negative arm (per1) and enhanced amplitude of the positive arm (bmal1) of clock machinery in retina. In addition to clock genes, miR-146a and its target gene IRAK1 also exhibited daily oscillations in antiphase; however, these patterns were lost in diabetic retina. This loss of rhythmic pattern was associated with an increase in ICAM-1, IL-β, and VEGF expression. Human retinal endothelial cells had robust miR-146a expression that followed circadian oscillation pattern; however, HRECs isolated from diabetic donors had reduced miR-146a amplitude but increased amplitude of IRAK1 and ICAM-1. In HRECs, miR-146a mimic or inhibitor caused 1.6- and 1.7-fold decrease or 1.5- and 1.6-fold increase, respectively, in mRNA and protein expression levels of ICAM-1 after 48 hours. CONCLUSIONS: Diabetes-induced dysregulation of daily rhythms of miR-146a and inflammatory pathways under miR-146a control have potential implications for the development of diabetic retinopathy.Item The Role of TGF-B Activated Kinase (TAK1) in Retinal Development and Inflammation(2021-08) Carrillo, Casandra; Belecky-Adams, Teri; Baucum, A.J.; Berbari, NicolasTransforming growth factor β-activated kinase 1 (TAK1), a hub kinase at the convergence of multiple signaling pathways, is critical to the development of the central nervous system and has been found to play a role in cell death and apoptosis. TAK1 may have the potential to elucidate mechanisms of cell cycle and neurodegeneration. The Belecky-Adams laboratory has aimed to study TAK1 and its potential roles in cell cycle by studying its role in chick retinal development as well as its possible implication in the progression of diabetic retinopathy (DR). Chapter 3 includes studies that explore TAK1 in a study in chick retinal development and TAK1 in in vitro studies in retinal microglia. Using the embryonic chick, immunohistochemistry for the activated form of TAK1 (pTAK1) showed localization of pTAK1 in differentiated and progenitor cells of the retina. Using an inhibitor or TAK1 activite, (5Z)-7-Oxozeaenol, in chick eye development showed an increase in progenitor cells and a decrease in differentiated cells. This study in chick suggests TAK1 may be a critical player in the regulation of the cell cycle during retinal development. Results from experimentation in chick led to studying the potential role of TAK1 in inflammation and neurodegeneration. TAK1 has previously been implicated in cell death and apoptosis suggesting that TAK1 may be a critical player in inflammatory pathways. TAK1 has been implicated in the regulation of inflammatory factors in different parts of the CNS but has not yet been studied specifically in retina or in specific retinal cells. Chapter 2 includes studies from the Belecky-Adams laboratory of in vitro work with retinal microglia. Retinal microglia were treated with activators and the translocation to the nucleus of a downstream factor of TAK1 was determined: NF-kB. Treatment of retinal microglia in the presence of activators with TAKinib, an inhibitor of TAK1 activation, revealed that TAK1 inhibition reduces the activation of downstream NF-kB. Together this data suggests that TAK1 may be implicated in various systems of the body and further studies on its mechanisms may help elucidate potential therapeutic roles of the kinase.