Mezu-Ndubuisi Research Group

The Developing Retina and Oxygen

Our eyes provide a unique window through which retinal blood vessels can be directly visualized. Premature infants are now being born at earlier gestational ages (as early as 22 weeks gestation) due to amazing new medical advances and clinical practice strategies, including surfactant replacement in immature lungs, gentler invasive and non-invasive ventilation methods, improved nutrition, and prevention of infection. However, premature birth exposes the still developing blood vessels of the fragile infant to harsh external stimuli and a relatively hyperoxic environment compared to the physiologically hypoxic in utero conditions. Hyperoxia disrupts blood vessel development in the retina, leading a condition called Retinopathy of Prematurity (ROP). In ROP, there is an initial loss of existing blood vessels following preterm birth, exacerbated by the use of supplemental oxygen for their respiratory insufficiency, which in subsequent weeks may lead to pathologic neovascularization, eventual bleeding and retinal detachment. Serial eye exams in the neonatal intensive care unit (NICU) help identify at risk infants for earlier treatment, but despite current management strategies, ROP remains one of the leading causes of childhood blindness worldwide.

In vivo Retinal Imaging in ROP

Although the etiology of ROP is multifactorial, the most significant risk factor is oxygen. The Mezu-Ndubuisi Research Group focuses on studying the effects of oxygen on the retina using newborn mice, who at full term birth are at the same developmental stage as premature babies born at 24 to 26 week gestation. Knowing that the retina can be visualized through an optically clear media, we discovered a way of studying ROP in mice without extracting the retina, leading to the development of an in vivo model of oxygen-induced retinopathy (OIR). In this model, we perform live imaging of the dilated eyes of anesthetized mice after oxygen exposure to directly visualize their retinal blood vessels at different stages of development. Our studies led to the novel use of in-vivo phosphorescence lifetime imaging to measure retinal vascular oxygen tension, fluorescein angiography (FA) to depict retinal vascular abnormalities, and spectral-domain optical coherence tomography (SD-OCT) to correlate retinal thickness changes to abnormal vascularization in a mouse model of OIR. Our lab’s use of in vivo retinal imaging helps delineate vessels more distinctly, and allows study of structural and functional changes from hyperoxia that could lead to neuronal dysfunction. It also enables longitudinal studies that could help limit the number of animals used. The mice are kept warm during live retinal imaging, which helps them to recover after imaging. We have also developed customized objective methods for quantitative analysis of the vascular features seen in vivo.

Video link to Dr. Mezu-Ndubuisi’s Grand Rounds Presentation titled: “Retinopathy of Prematurity: From Bench to Bedside – Insights from In Vivo Imaging”

Clinical and Therapeutic Application of In vivo Imaging

The Mezu-Ndubuisi Research Group studies the correlation between the effects of oxidative stress in the retina and other developing organs, like the lung and kidneys, and investigates the signaling mechanisms involved in these complex interactions. We are expanding our research to include therapeutic testing and the use of genetic modification to reduce the susceptibility of developing tissues to oxidative injury. This will hopefully lead to development of safe therapies, as well as biomarkers to enable prevention, earlier detection, and more effective treatment for this visually handicapping disease in our fragile population of premature children.

Lab figures
Representative image of Simultaneous In vivo FA, SD-OCT, and ERG shows acute (P19) and long-term (P47) changes in retinal vascularization, structure and function respectively in RA and OIR mice. At P19 in OIR mice, FA shows capillary avascularity, dilated veins, and tortuous arteries, SD-OCT shows retinal thinning localized to the inner retina, ERG shows abnormal synaptic interactions/signal transmission Histology shows neovascularization (red double arrow), inner retinal thinning and disorganized retina architecture, particularly the outer retina. Immunohistochemistry shows ectopically aligned synapses in the outer plexiform layer (OPL) between the rod bipolar cell (red protein kinase C alpha (PKC-alpha) stain) and the photoreceptor cells (green postsynaptic density protein 95 (PSD95) stain). P19 RA mice show normal vessel caliber, full capillary vascularity, normal retinal structure and function in RA mice, in contrast. At P47, OIR mice have persistent vascular, structural and functional abnormalities compared to age-matched RA mice. In FA images, blue arrows (veins), red arrows (arteries), white (capillaries), green circle (region of interest for SD-OCT and ERG measurements). In the histology, GCL denotes Ganglion cell layer, INL denotes inner nuclear layer; IPL denotes inner plexiform layer; OPL denotes outer plexiform layer; ONL denotes outer nuclear layer.

Additional Research Activities

Clinical Research Interests: Prevention of ROP and bronchopulmonary dysplasia (BPD) in premature babies, and improving nutrition in very low birth weight babies in the NICU.

UW Global Health Institute: Dr. Mezu-Ndubuisi is actively involved in research on global health disparities and participates in international medical missions.

Lab News

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    1. Ascierto PA, Fox B, Urba W, Anderson AC, Atkins MB, Borden EC, Brahmer J, Butterfield LH, Cesano A, Chen D, de Gruijl T, Dillman RO, Drake CG, Emens LA, Gajewski TF, Gulley JL, Stephen …

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