Area of Research Focus

Age-Associated Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in individuals over the age of 50, particularly in industrialized nations. The etiology of AMD is multifactorial, involving genetic susceptibility—such as polymorphisms in CFH, ARMS2, and HTRA1—as well as environmental factors like smoking, poor diet, and oxidative stress. Globally, AMD affects nearly 200 million people, with prevalence expected to rise significantly due to aging populations. The pathophysiology of AMD is hallmarked by the accumulation of drusen between the retinal pigment epithelium (RPE) and Bruch’s membrane, leading to RPE dysfunction, photoreceptor loss, and, in advanced stages, geographic atrophy or choroidal neovascularization.

Current treatment for wet AMD primarily involves intravitreal injections of anti-VEGF agents (e.g., ranibizumab, aflibercept, and faricimab), which inhibit abnormal blood vessel growth and reduce vascular leakage. For dry AMD, therapeutic options remain limited, but recent advances include the FDA-approved complement C3 inhibitor pegcetacoplan and C5 inhibitor avacincaptad pegol, which aim to slow the progression of geographic atrophy. Nutritional supplementation with antioxidants and zinc, as recommended by the AREDS2 study, also remains a cornerstone of early-stage dry AMD management. These evolving strategies reflect a growing emphasis on targeted, mechanism-based interventions to preserve vision and retinal health.

Research conducted by the Bu lab continues to focus on the role of mitochondrial dysfunction and oxidative stress in RPE degeneration. Her studies support mitochondrial DNA damage and impaired mitophagy as key contributors to RPE cell death and inflammation. Therapeutic potential of mitochondrial-targeted antioxidants, such as SkQ1 and MitoQ, show promise in preserving mitochondrial integrity and reducing oxidative injury in preclinical AMD models. These findings support the development of mitochondria-focused interventions as a novel therapeutic avenue. Drs. Stubbs and Bu have contributed important insights into the potential role of statins in the prevention and progression of AMD. Their collaborative research has explored how statins—widely used lipid-lowering agents—may influence AMD pathogenesis through mechanisms beyond cholesterol regulation. Specifically, their studies have examined the anti-inflammatory and antioxidant properties of statins, as well as their effects on retinal pigment epithelium (RPE) health and drusen formation. Dr. Bu’s work has highlighted how statins may modulate mitochondrial function and reduce oxidative stress in RPE cells, potentially mitigating cellular damage associated with early AMD. Meanwhile, Dr. Stubbs has investigated the epidemiological and translational aspects, analyzing patient data to assess correlations between statin use and AMD incidence or progression. Together, their findings suggest that statins may offer a protective effect in certain AMD subtypes, although further clinical trials are needed to clarify their therapeutic potential and identify which patient populations may benefit most.

Description

Primary Open Angle Glaucoma
Normal Tension Glaucoma

Primary open-angle glaucoma (POAG) is a chronic, progressive optic neuropathy characterized by the gradual loss of retinal ganglion cells and their axons, leading to visual field defects and potentially irreversible blindness. It is the most common form of glaucoma, affecting approximately 3% of the global population over the age of 40. A subtype, normal-tension glaucoma (NTG), occurs despite intraocular pressure (IOP) remaining within the statistically normal range and is particularly prevalent in certain populations, such as individuals of East Asian descent. The etiology of POAG is multifactorial, involving both genetic and environmental factors.

While elevated IOP is the most significant risk factor, typically resulting from impaired aqueous humor outflow through the trabecular meshwork and Schlemm’s canal, the presence of NTG highlights additional pathogenic mechanisms such as vascular dysregulation, oxidative stress, and neuroinflammation. A key component of the pathophysiology is reactive astrocytosis, in which astrocytes in the optic nerve head become activated in response to stress or injury. This process contributes to extracellular matrix remodeling, release of pro-inflammatory cytokines, and disruption of axonal support, thereby exacerbating retinal ganglion cell damage. Mechanical and ischemic injury at the lamina cribrosa further impairs axonal transport, leading to progressive optic nerve cupping. Early detection and management are essential to slow disease progression and preserve vision.

The collaborative research of Drs. Stubbs, Kaja, Rao, Hong, and Chaku has significantly advanced the understanding of glaucoma pathophysiology, with a particular focus on neuroinflammatory mechanisms and extracellular matrix remodeling. Through the use of cell culture, experimental animal models, and detailed molecular analyses, they have elucidated the role of oxidative stress, cytokine signaling, and extracellular matrix alterations in the pathophysiology of POAG. Notably, their investigations have explored the therapeutic potential of mitochondrial-targeted antioxidants, which aim to mitigate oxidative damage and preserve mitochondrial function within the trabecular meshwork. Additional studies by this team highlights the role of reactive astrocytosis and glial activation in the progression of retinal ganglion cell degeneration, emphasizing the contribution of non-IOP-dependent factors in both primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG). By protecting mitochondrial health, mitochondrial-targeted antioxidants may help maintain aqueous humor outflow and reduce intraocular pressure, offering a dual mechanism of neuroprotection and pressure regulation. These findings support the development of comprehensive treatment strategies targeting both neural and outflow pathways, underscoring the importance of early intervention beyond IOP control. This body of work contributes to a growing paradigm shift in glaucoma research, moving toward a more integrated, cell-based understanding of disease progression.

Publications

2023

Iezhitsa IN, Agarwal R, Agarwal P, Srivastava K, Dorovskikh V, Spasov A, Krushinskaya Y, Bouchard CS, Bu P, Spasova N, Kutko R, Azizov P, Zheltova A, Yeritsyan N, Lin S. The potential role of oxidative stress in the pathogenesis of primary open-angle glaucoma: Therapeutic perspectives. Frontiers in Pharmacology. 2023 Feb 16;14:1121848. doi:10.3389/fphar.2023.1121848. PMID: 36874797; PMCID: PMC9974829.

2022

Iezhitsa IN, Agarwal R, Agarwal P, Spasov A, Bouchard CS, Bu P, Kutko R, Ibragimova L, Krushinskaya Y, Azizov P, Zheltova A, Yeritsyan N, Lin S. Magnesium and Experimental Glaucomatous Optic Neuropathy: Clinical and Experimental Evidence. Frontiers in Pharmacology. 2022 Oct 7;13:1005796. doi:10.3389/fphar.2022.1005796. PMID: 36275094; PMCID: PMC9589766.

2021

Iezhitsa IN, Agarwal R, Agarwal P, Spasov A, Bouchard CS, Bu P, Kutko R, Ibragimova L, Krushinskaya Y, Azizov P, Zheltova A, Yeritsyan N, Lin S. Magnesium and Experimental Glaucomatous Optic Neuropathy: Clinical and Experimental Evidence. Frontiers in Pharmacology. 2021; 12: 1005796. [Epub ahead of print, later republished in 2022].
Rao VR, Stubbs Jr. EB. TGF-β2 promotes oxidative stress in human trabecular meshwork cells by selectively enhancing NADPH Oxidase 4 expression. Submitted, 2021.

2020

Ghosh AK, Rao VR, Wisniewski VJ, Zigrossi AD, Floss J, Koulen P, Stubbs Jr. EB, Kaja S. Differential activation of glioprotective intracellular signaling pathways in primary optic nerve head astrocytes after treatment with different classes of antioxidant. Antioxidants. 2020; 9(4): 324. doi:10.3390/antiox9040324.

2019

Rao VR, Lautz JD, Foecking EM, Lukacs EA, Kaja S, Stubbs Jr. EB. Mitochondrial-targeted antioxidants attenuate TGF-β2 canonical signaling in human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2019; 60: 3613–3624. doi:10.1167/iovs.19-27542.

2018

Keller KE, Bhattacharya SK, … Stubbs Jr. EB, … Stamer WD. Consensus recommendations for trabecular meshwork cell isolation, characterization and culture. Exp Eye Res. 2018; pii: S0014-4835(18)30153-2. doi:10.1016/j.exer.2018.03.001.

2017

Stubbs Jr. EB. Isoprenylation of monomeric GTPases in human trabecular meshwork cells. Methods Mol Biol. 2017; 1609: 217–229. doi:10.1007/978-1-4939-6996-8_18.

Description

Ischemic retinopathy encompasses a group of vision-threatening retinal disorders caused by insufficient blood flow and oxygen delivery to retinal tissues. Common forms include diabetic retinopathy, retinal vein occlusion, and ocular ischemic syndrome. The pathophysiology is driven by capillary non-perfusion, endothelial dysfunction, and hypoxia-induced upregulation of angiogenic and inflammatory mediators such as vascular endothelial growth factor (VEGF) and interleukins. This cascade leads to neovascularization, increased vascular permeability, retinal edema, and eventual neurovascular degeneration.

The collaborative research team of Drs. Bu, McDonnell, and de Alba has advanced the understanding of ischemic retinopathy by integrating molecular, neurophysiological, and clinical perspectives—highlighting the roles of mitochondrial dysfunction, neurovascular compromise, and therapeutic response monitoring in the progression and management of retinal ischemia. Dr. Bu’s research has elucidated the role of mitochondrial dysfunction and oxidative stress in ischemia-induced retinal injury, demonstrating that mitochondrial damage in retinal endothelial and glial cells contributes to reactive oxygen species (ROS) accumulation, inflammation, and blood-retinal barrier breakdown. Her work has also explored the therapeutic potential of mitochondrial-targeted antioxidants to mitigate these effects. Dr. McDonnell has contributed to the understanding of ischemic retinopathy through his investigations into retinal neurovascular coupling and the impact of chronic ischemia on retinal ganglion cell survival, emphasizing the importance of early neuroprotective intervention. Dr. de Alba’s clinical research has focused on optimizing anti-VEGF treatment protocols and imaging biomarkers to monitor disease progression and therapeutic response in ischemic retinal diseases, particularly in diabetic retinopathy and retinal vein occlusion. Together, these contributions highlight the multifaceted nature of ischemic retinopathy and support a growing emphasis on integrated therapeutic strategies that combine vascular stabilization, neuroprotection, and mitochondrial preservation.

2018

Stubbs Jr. EB., Fisher MA, Miller CM, Jelinek C, Butler J, McBurney C, Collins EG. Randomized controlled trial of physical exercise in diabetic Veterans with length-dependent distal symmetric polyneuropathy. Frontiers in Neuroscience (minor revisions, 2018).

2016

Jolivalt CG, Frizzi KE, Guernsey L, Marquez A, Ochoa J, Rodriguez M, Calcutt NA, Toth C, Siao Tick Chong M, Hunter N, Rosenberg H, Jolivalt N, Echeverry S, Stubbs Jr. EB. Peripheral neuropathy in mouse models of diabetes is associated with oxidative stress, reduced axonal transport and mitochondrial dysfunction. PLoS One. 2016; 11(4): e0153381. doi:10.1371/journal.pone.0153381. PMID: 27071086; PMCID: PMC4829167.

2011

Shankarappa SA, Piedras-Rentería ES, Stubbs Jr. EB. Forced-exercise delays neuropathic pain in experimental diabetes: Effects on voltage-gated calcium channels. Neurochemistry International. 2011; 118: 224-236.

2005

Emerick AJ, Richards MP, Kartje GL, Neafsey EJ, Stubbs Jr. EB. Experimental diabetes attenuates cerebral cortical-evoked forelimb motor responses. Diabetes. 54:2764–2771.

Description

Peripheral neuropathy is a common neurological disorder resulting from damage to the peripheral nerves, affecting sensory, motor, and autonomic pathways. Its etiology is broad, encompassing diabetes mellitus (the most prevalent cause), chronic alcohol use, vitamin deficiencies, autoimmune conditions, infections, hereditary disorders, and exposure to neurotoxic agents. Globally, peripheral neuropathy affects approximately 2–7% of the population, with significantly higher rates among individuals with diabetes. The pathophysiology of PN involves axonal degeneration, demyelination, or both, leading to impaired nerve conduction and progressive functional deficits. In diabetic neuropathy, chronic hyperglycemia induces oxidative stress, microvascular injury, and inflammation, contributing to nerve ischemia and metabolic dysfunction.

Dr. Stubbs’ lab has made notable contributions to the field through his research on both metabolic neuropathies and immune-mediated conditions such as Guillain-Barré syndrome (GBS). His experimental animal studies on GBS have explored the immunopathogenesis of AIDP, focusing on the role of molecular mimicry, complement activation, and inflammatory cytokine cascades in peripheral nerve injury. Stubbs has also investigated early electrophysiological markers and cerebrospinal fluid profiles that may aid in the timely diagnosis and differentiation of GBS variants. Notably, his work has investigated the potential role of statins—traditionally used for lipid-lowering—as immunomodulatory agents in the management of GBS. His studies suggest that statins may attenuate inflammatory responses and complement-mediated nerve damage, offering a novel adjunctive therapeutic strategy. In the context of diabetic neuropathy, Stubbs has investigated how systemic metabolic stressors—such as insulin resistance and dyslipidemia—exacerbate peripheral nerve degeneration, with a particular focus on mitochondrial dysfunction and impaired axonal transport. Importantly, his collaborative studies have also examined the impact of structured exercise interventions on the progression of diabetic neuropathy. His findings suggest that regular aerobic and resistance training can improve nerve conduction velocity, reduce inflammatory markers, and enhance mitochondrial function in peripheral nerves. These results support exercise not only as a preventive strategy but also as a disease-modifying intervention in diabetic neuropathy. Collectively, Stubbs’ work underscores the importance of integrating metabolic control, immunomodulation, and lifestyle interventions in the comprehensive management of peripheral neuropathies.

Publications

2020

Stubbs Jr. EB. Targeting the blood-nerve barrier for the management of immune-mediated peripheral neuropathies. Experimental Neurology. 2020; 331: 113385. doi:10.1016/j.expneurol.2020.113385. PMID: 32562668.

2017

Langert KA, Goshu B, Stubbs Jr. EB. Attenuation of experimental autoimmune neuritis with locally administered lovastatin-encapsulating PLGA nanoparticles. Neurochemistry International. 2017; 140: 334-346. doi:10.1016/j.neuint.2017.08.005. PMID: 28803812.

2016

Ubogu EE, Cossoy MB, Renaud S, Hartung HP, Herrmann DN, Hughes RAC, Saperstein DS, Sommer C, van Doorn PA, Wanschitz J, Stubbs Jr. EB, Zochodne DW, Latov N. The immunopathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy: Implications for therapy. Expert Review of Clinical Immunology. 2016; 12(3): 267–278. doi:10.1586/1744666X.2016.1123096. PMID: 26632549.

2015

Calik MW, Shankarappa SA, Langert KA, Stubbs Jr. EB. Forced-exercise preconditioning attenuates experimental autoimmune neuritis by altering Th1 lymphocyte composition and egress. ASN Neuro. July–August: 1–11.

2014

Langert KA, Pervan CL, Stubbs Jr. EB. Novel role of Cdc42 and RalA GTPases in tumor necrosis factor-α mediated secretion of CCL2. Small GTPases. 2014; 5(4). doi:10.4161/sgtp.29260. PMID: 25483253.
Ubogu EE, Cossoy MB, Renaud S, Hartung HP, Herrmann DN, Hughes RAC, Saperstein DS, Sommer C, van Doorn PA, Wanschitz J, Stubbs Jr. EB, Zochodne DW, Latov N. The immunopathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy: Implications for therapy. Expert Review of Clinical Immunology. 2014; 10(5): 547–566. doi:10.1586/1744666X.2014.897325. PMID: 24628491.

2013

Langert KA, Von Zee CL, Stubbs Jr. EB. Cdc42 GTPases facilitate Tumor Necrosis Factor-α mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells. Journal of the Peripheral Nervous System. 2013; 18(3): 199-208. doi:10.1111/jns5.12027. PMID: 24033617.

2002

Lawlor MA, Richards MP, De Vries GH, Fisher MA, Stubbs Jr. EB. Antibodies to L-periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits. 83:592–600.