IU Indianapolis ScholarWorks :: Browsing by Subject "Retina"

Browsing by Subject "Retina"

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Asian Race and Primary Open-Angle Glaucoma: Where Do We Stand?
(MDPI, 2022-04-28) Belamkar, Aditya; Harris, Alon; Oddone, Francesco; Verticchio Vercellin, Alice; Fabczak-Kubicka, Anna; Siesky, Brent; Ophthalmology, School of Medicine
Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by irreversible retinal ganglion cell damage and visual field loss. The global POAG prevalence is estimated to be 3.05%, and near term is expected to significantly rise, especially within aging Asian populations. Primary angle-closure glaucoma disproportionately affects Asians, with up to four times greater prevalence of normal-tension glaucoma reported compared with high-tension glaucoma. Estimates for overall POAG prevalence in Asian populations vary, with Chinese and Indian populations representing the majority of future cases. Structural characteristics associated with glaucoma progression including the optic nerve head, retina, and cornea are distinct in Asians, serving as intermediates between African and European descent populations. Patterns in IOP suggest some similarities between races, with a significant inverse relationship between age and IOP only in Asian populations. Genetic differences have been suggested to play a role in these differences, however, a clear genetic pattern is yet to be established. POAG pathogenesis differs between Asians and other ethnicities, and it may differ within the broad classification of the Asian race. Greater awareness and further research are needed to improve treatment plans and outcomes for the increasingly high prevalence of normal tension glaucoma within aging Asian populations.
Aster proteins mediate carotenoid transport in mammalian cells
(National Academy of Science, 2022) Bandara, Sepalika; Ramkumar, Srinivasagan; Imanishi, Sanae; Thomas, Linda D.; Sawant, Onkar B.; Imanishi, Yoshikazu; von Lintig, Johannes; Ophthalmology, School of Medicine
Some mammalian tissues uniquely concentrate carotenoids, but the underlying biochemical mechanism for this accumulation has not been fully elucidated. For instance, the central retina of the primate eyes displays high levels of the carotenoids, lutein, and zeaxanthin, whereas the pigments are largely absent in rodent retinas. We previously identified the scavenger receptor class B type 1 and the enzyme β-carotene-oxygenase-2 (BCO2) as key components that determine carotenoid concentration in tissues. We now provide evidence that Aster (GRAM-domain-containing) proteins, recently recognized for their role in nonvesicular cholesterol transport, engage in carotenoid metabolism. Our analyses revealed that the StART-like lipid binding domain of Aster proteins can accommodate the bulky pigments and bind them with high affinity. We further showed that carotenoids and cholesterol compete for the same binding site. We established a bacterial test system to demonstrate that the StART-like domains of mouse and human Aster proteins can extract carotenoids from biological membranes. Mice deficient for the carotenoid catabolizing enzyme BCO2 concentrated carotenoids in Aster-B protein-expressing tissues such as the adrenal glands. Remarkably, Aster-B was expressed in the human but not in the mouse retina. Within the retina, Aster-B and BCO2 showed opposite expression patterns in central versus peripheral parts. Together, our study unravels the biochemical basis for intracellular carotenoid transport and implicates Aster-B in the pathway for macula pigment concentration in the human retina.
Astrocytes modulate neurodegenerative phenotypes associated with glaucoma in OPTN(E50K) human stem cell-derived retinal ganglion cells
(Elsevier, 2022) Gomes, Cátia; VanderWall, Kirstin B.; Pan, Yanling; Lu, Xiaoyu; Lavekar, Sailee S.; Huang, Kang-Chieh; Fligor, Clarisse M.; Harkin, Jade; Zhang, Chi; Cummins, Theodore R.; Meyer, Jason S.; Medical and Molecular Genetics, School of Medicine
Although the degeneration of retinal ganglion cells (RGCs) is a primary characteristic of glaucoma, astrocytes also contribute to their neurodegeneration in disease states. Although studies often explore cell-autonomous aspects of RGC neurodegeneration, a more comprehensive model of glaucoma should take into consideration interactions between astrocytes and RGCs. To explore this concept, RGCs and astrocytes were differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated OPTN(E50K) mutation along with corresponding isogenic controls. Initial results indicated significant changes in OPTN(E50K) astrocytes, including evidence of autophagy dysfunction. Subsequently, co-culture experiments demonstrated that OPTN(E50K) astrocytes led to neurodegenerative properties in otherwise healthy RGCs, while healthy astrocytes rescued some neurodegenerative features in OPTN(E50K) RGCs. These results are the first to identify disease phenotypes in OPTN(E50K) astrocytes, including how their modulation of RGCs is affected. Moreover, these results support the concept that astrocytes could offer a promising target for therapeutic intervention in glaucoma.
Astrocytes Regulate the Development and Maturation of Retinal Ganglion Cells Derived from Human Pluripotent Stem Cells
(Elsevier, 2019-02-12) VanderWall, Kirstin B.; Vij, Ridhima; Ohlemacher, Sarah K.; Sridhar, Akshayalakshmi; Fligor, Clarisse M.; Feder, Elyse M.; Edler, Michael C.; Baucum, Anthony J.; Cummins, Theodore R.; Meyer, Jason S.; Biology, School of Science
Retinal ganglion cells (RGCs) form the connection between the eye and the brain, with this connectivity disrupted in numerous blinding disorders. Previous studies have demonstrated the ability to derive RGCs from human pluripotent stem cells (hPSCs); however, these cells exhibited some characteristics that indicated a limited state of maturation. Among the many factors known to influence RGC development in the retina, astrocytes are known to play a significant role in their functional maturation. Thus, efforts of the current study examined the functional maturation of hPSC-derived RGCs, including the ability of astrocytes to modulate this developmental timeline. Morphological and functional properties of RGCs were found to increase over time, with astrocytes significantly accelerating the functional maturation of hPSC-derived RGCs. The results of this study clearly demonstrate the functional and morphological maturation of RGCs in vitro, including the effects of astrocytes on the maturation of hPSC-derived RGCs.
Automated Microaneurysms Detection in Retinal Images Using Radon Transform and Supervised Learning: Application to Mass Screening of Diabetic Retinopathy
(IEEE, 2021) Tavakoli, Meysam; Mehdizadeh, Alireza; Aghayan, Afshin; Shahri, Reza Pourreza; Ellis, Tim; Dehmeshki, Jamshid; Physics, School of Science
Detection of red lesions in color retinal images is a critical step to prevent the development of vision loss and blindness associated with diabetic retinopathy (DR). Microaneurysms (MAs) are the most frequently observed and are usually the first lesions to appear as a consequence of DR. Therefore, their detection is necessary for mass screening of DR. However, detecting these lesions is a challenging task because of the low image contrast, and the wide variation of imaging conditions. Recently, the emergence of computer-aided diagnosis systems offers promising approaches to detect these lesions for diagnostic purposes. In this paper we focus on developing unsupervised and supervised techniques to cope intelligently with the MAs detection problem. In the first step, the retinal images are preprocessed to remove background variation in order to achieve a high level of accuracy in the detection. In the main processing step, important landmarks such as the optic nerve head and retinal vessels are detected and masked using the Radon transform (RT) and multi-overlapping windows. Finally, the MAs are detected and numbered by using a combination of RT and a supervised support vector machine classifier. The method was tested on three publicly available datasets and a local database comprising a total of 749 images. Detection performance was evaluated using sensitivity, specificity, and FROC analysis. From the image analysis viewpoint, DR was detected with a sensitivity of 100% and a specificity of 93% on average across all of these databases. Moreover, from lesion-based analysis the proposed approach detected the MAs with sensitivity of 95.7% with an average of 7 false positives per image. These results compare favourably with the best of the published results to date.
Blood flow regulation and oxygen transport in a heterogeneous model of the mouse retina
(Elsevier, 2020-11) Fry, Brendan C.; Harris, Alon; Siesky, Brent; Arciero, Julia; Mathematical Sciences, School of Science
Elevated intraocular pressure is the primary risk factor for glaucoma, yet vascular health and ocular hemodynamics have also been established as important risk factors for the disease. The precise physiological mechanisms and processes by which flow impairment and reduced tissue oxygenation relate to retinal ganglion cell death are not fully known. Mathematical modeling has emerged as a useful tool to help decipher the role of hemodynamic alterations in glaucoma. Several previous models of the retinal microvasculature and tissue have investigated the individual impact of spatial heterogeneity, flow regulation, and oxygen transport on the system. This study combines all three of these components into a heterogeneous mathematical model of retinal arterioles that includes oxygen transport and acute flow regulation in response to changes in pressure, shear stress, and oxygen demand. The metabolic signal (Si) is implemented as a wall-derived signal that reflects the oxygen deficit along the network, and three cases of conduction are considered: no conduction, a constant signal, and a flow-weighted signal. The model shows that the heterogeneity of the downstream signal serves to regulate flow better than a constant conducted response. In fact, the increases in average tissue PO2 due to a flow-weighted signal are often more significant than if the entire level of signal is increased. Such theoretical work supports the importance of the non-uniform structure of the retinal vasculature when assessing the capability and/or dysfunction of blood flow regulation in the retinal microcirculation.
BMP Pathway and Reactive Retinal Gliosis
(2013-03-06) Dharmarajan, Subramanian; Belecky-Adams, Teri; Skalnik, David Gordon; Zhang, Xin; Atkinson, Simon
Reactive gliosis is known to have a beneficial and a degenerative effect following injury to neurons. Although many factors have been implicated in reactive gliosis, their role in regulating this change is still unclear. We investigated the role of bone morphogenetic proteins in reactive gliosis in vivo and in vitro. In vivo, IHC analysis indicated reactive gliosis in the 6 week Ins2Akita mouse and WPK rat retinas. Expression of BMP7 was upregulated in these models, leading to an increase in the phosphorylation of downstream SMAD1. In vitro, treatment of murine retinal astrocyte cells with a strong oxidizing agent such as sodium peroxynitrite regulated RNA levels of various markers, including GFAP, CSPGs, MMPs and TIMPs. BMP7 treatment also regulated RNA levels to a similar extent, suggesting reactive gliosis. Treatment with high glucose DMEM and BMP4, however, did not elicit increase in levels to a similar degree. Increase in SMAD levels and downstream targets of SMAD signaling such as ID1, ID3 and MSX2 was also observed following treatment with sodium peroxynitrite in vitro and in the 6 week Ins2Akita mouse retinas in vivo. These data concur with previously established data which show an increase in BMP7 levels following injury. It also demonstrates a role for BMP7 in gliosis following disease. Further, it suggests SMAD signaling to play a role in initiating reactivity in astrocytes as well as in remodeling the extracellular matrix following injury and in a disease condition.
Build your own retina: modeling retinogenesis and disease using human pluripotent stem cells
(2017) Sridhar, Akshayalakshmi; Meyer, Jason
Human pluripotent stem cells (hPSCs) allow for the unprecedented ability to recapitulate early stages of human development, which are otherwise inaccessible to investigation. This is especially true for one of the earliest events in human development, the establishment of a neuroretinal fate from an unspecified pluripotent population. To test the ability of hPSCs to serve in this capacity, hPSCs were generated using mRNA-reprogamming methods and maintained in xenogeneic-free differentiation conditions. These cells were directed to differentiate using a three-dimensional approach to analyze their ability to successfully recapitulate early events in human development in a temporal and developmentally-appropriate fashion. To do so, hPSCs were first directed to an anterior neural phenotype, which was confirmed by analysis of stage-specific neural transcription factors via immunocytochemistry and quantitative RT-PCR. Next, the cells were directed to an optic vesicle-like stage, where the presumptive retinal cells were identified by the expression of specific transcription factors. Finally, three-dimensional optic vesicle-like retinal organoids were identified, isolated, and further analyzed for the expression of markers associated with some of the differentiated cell types of the neural retina. Upon establishment of hPSC-derived retinal organoids, this system was further utilized to study the neurodegeneration in glaucoma and provide insights into the disease mechanisms. Overall, the results of this study help to demonstrate the suitability of hPSC-differentiation approaches as an effective tool to model retinal development and disease.
Circadian Rhythm Disruption Results in Visual Dysfunction
(Wiley, 2022-02-07) Mathew, Deepa; Luo, Qianyi; Bhatwadekar, Ashay D.; Ophthalmology, School of Medicine
Artificial light has been increasingly in use for the past 70 years. The aberrant light exposure and round‐the‐clock nature of work lead to the disruption of biological clock. Circadian rhythm disruption (CRD) contributes to multiple metabolic and neurodegenerative diseases. However, its effect on vision is not understood. Moreover, the mammalian retina possesses an autonomous clock that could be reset with light exposure. We evaluated the impact of CRD on retinal morphology, physiology, and vision after housing mice in a disruption inducing shorter light/dark cycle (L10:D10). Interestingly, the mice under L10:D10 exhibited three different entrainment behaviors; “entrained,” “free‐running,” and “zigzagging.” These behavior groups under CRD exhibited reduced visual acuity, retinal thinning, and a decrease in the number of photoreceptors. Intriguingly, the electroretinogram response was decreased only in the mice exhibiting “entrained” behavior. The retinal proteome showed distinct changes with each entrainment behavior, and there was a dysfunctional oxidative stress‐antioxidant mechanism. These results demonstrate that CRD alters entrainment behavior and leads to visual dysfunction in mice. Our studies uniquely show the effect of entrainment behavior on retinal physiology. Our data have broader implications in understanding and mitigating the impact of CRD on vision and its potential role in the etiology of retinal diseases.
Dapagliflozin protects neural and vascular dysfunction of the retina in diabetes
(BMJ, 2022) Luo, Qianyi; Leley, Sameer P.; Bello, Erika; Dhami, Hurshdeep; Mathew, Deepa; Bhatwadekar, Ashay Dilip; Ophthalmology, School of Medicine
Introduction: Dapagliflozin, a sodium-glucose transporter inhibitor, effectively reduces blood glucose and is indicated for individuals with kidney diseases and cardiovascular disorders. In this study, we further expand the therapeutic benefit of dapagliflozin in the neural and vascular retina, with the potential to effectively manage diabetic retinopathy (DR), the most common complication of diabetes. Research design and methods: Db/db mice, an animal model of type 2 diabetes, were treated with dapagliflozin orally, and the electroretinogram (ERG) response and acellular capillary numbers were assessed. Messenger RNA levels of inflammatory cytokines were studied using real-time quantitative (q)PCR. We assessed endothelial cell migration in a scratch wound assay and retinal glucose uptake using human retinal endothelial cells. Results: The dapagliflozin treatment improved the ERG b-wave amplitude and decreased acellular capillary numbers. The scratch wound assay demonstrated a reduction in wound closure after dapagliflozin treatment. Retinal glucose uptake reduced after dapagliflozin treatment compared with the respective controls. Conclusions: Our studies suggest that dapagliflozin treatment effectively corrects neural and vascular dysfunction of the retina in diabetes. This effect is mediated by a decrease in inflammation and improved glycemic control. In addition, dapagliflozin exhibits decreased wound healing and glucose uptake, which could benefit the retina. Thus, dapagliflozin could be helpful in the management of DR, with multimodal therapeutic effects.

Browsing by Subject "Retina"

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