Credentials

Undergraduate:

B.S., Chemistry, Biochemistry – University of Illinois at Champaign-Urbana, Champaign-Urbana, IL

Graduate:

Ph.D., Biochemistry – University of Missouri, Columbia, MO

Postgraduate:

Postdoctoral Fellow – Neuroscience Laboratory; Mental Health Research Institute, University of Michigan, Ann Arbor, MI

Research Focus: Glaucoma, Neuroscience

Summary of Research Interests

Generous support from various funding agencies including the Department of Veterans Affairs, National Institutes of Health, and several private foundations have allowed the Stubbs lab to pursue our primary research interests focused on developing novel therapeutic strategies for the clinical management of neuropathies. One such strategy being developed in the Stubbs lab utilizes a novel nanoparticle-based local drug delivery platform for the treatment of Guillain-Barré Syndrome (GBS), a prominent and debilitating acute inflammatory demyelinating disorder of the peripheral nervous system (AIDP). Our recently published experimental studies demonstrate that peri-neural administration of lovastatin-encapsulating PLGA nanoparticles significantly attenuate the clinical severity of EAN, an established animal model of AIDP/GBS. Statin-associated neuroprotection was found to significantly limit transendothelial trafficking of autoreactive leukocytes into peripheral nerve by disrupting isoprenylation of Rho GTPases. Statins similarly were found to alter Rho GTPase signaling in primary human trabecular meshwork (TM) cells. Human TM cells play a key role in regulating aqueous humor (AH) outflow / intraocular pressure. For reasons that remain unclear, AH outflow through the trabecular meshwork is impaired in patients with primary open angle glaucoma (POAG) leading to elevated intraocular pressure and ultimately glaucomatous neuropathy. Using our nanoparticles as a platform, we are able to deliver deep within the TM various encapsulated therapeutic agents, including novel mitochondrial-targeted antioxidants. It is here where these agents may have the greatest therapeutic impact for the management of POAG by minimizing or preventing oxidative-injury associated increases in outflow resistance. A third neuropathic disorder that the Stubbs lab studies in association with clinical colleagues is diabetic neuropathy, a very common metabolic neuropathy that significantly alters the quality of life for millions of people worldwide. Bringing together specialists in neurology and exercise physiology, we successfully conducted a VA-funded single site randomized clinical trial looking at the impact that moderate-intensity aerobic or strength-training exercise elicits on the progression of polyneuropathy among glycemic-controlled type 2 diabetic Veterans. Qualitative findings from this study suggest that a short-term (12-week) course of aerobic physical exercise may very well improve sensory, but not motor, nerve fiber function independent of glycemic control. Although the mechanism for this remains speculative, our experimental studies show that aerobic exercise can significantly delay the onset of neuropathic pain, in part, by attenuating calcium channel function within small diameter DRG neurons by altering opioidergic tone.

Publications

Glaucomatous Optic Neuropathy

• Rao VR & Stubbs Jr. EB. TGF-β2 Promotes Oxidative Stress in Human Trabecular Meshwork Cells by Selectively Enhancing NADPH Oxidase 4 Expression. Investigative ophthalmology & visual science. 2021 April. 62(4): 4. https://doi.org/10.1167/iovs.62.4.4. PMID: 33821883. PMCID: PMC8039474.
• 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, 324; doi:10.3390/antiox9040324.
• 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.
• 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.
• 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.
• Ghosh AK, Thapa R, Hariani HN, Volyanyuk M, Ogle SD, Orloff KA, Ankireddy S, Lai K, Žiniauskaitė A, Stubbs EB Jr., Kalesnykas G, Hakkarainen JJ, Langert KA, Kaja S. Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress. Pharmaceutics. 2021 August; 13(9):1362. doi.org/10.3390/pharmaceutics13091362. PMID: 34575438. PMCID: PMC8471707.

Immune-Mediated Peripheral Neuropathy

• Stubbs Jr. EB. Targeting the blood-nerve barrier for the management of immune-mediated peripheral neuropathies. Exp. Neurology 2020. Doi.org/10.1016/j.expneurol.2020.113385.
• Langert KA, Goshu B, Stubbs Jr. EB. Attenuation of experimental autoimmune neuritis with locally administered lovastatin-encapsulating PLGA nanoparticles. J. Neurochem. 2017: 140;334-346.
• Langert KA, Pervan CL, and Stubbs Jr. EB. Novel role of Cdc42 and RalA GTPases in tumor necrosis factor-α mediated secretion of CCL2. Small GTPases 2014:5; doi:10.4161/sgtp.29260.
• Langert KA, Von Zee CL, and Stubbs Jr. EB. Cdc42 GTPases facilitate Tumor Necrosis Factor-α mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells. J. Perph. Nerv. System 2013, 18(3):199-208.

Diabetic Neuropathy

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

Additional Significant Contributions

• Ghosh AK, Thapa R, Hariani HN, Volyanyuk M, Ogle SD, Orloff KA, Ankireddy S, Lai K, Žiniauskaitė A, Stubbs EB Jr., Kalesnykas G, Hakkarainen JJ, Langert KA, Kaja S. Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress. Pharmaceutics. 2021 August; 13(9):1362. doi.org/10.3390/pharmaceutics13091362. PMID: 34575438. PMCID: PMC8471707.
• 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 2015, July-August:1-11.
• Emerick AJ, Richards MP, Kartje GL, Neafsey EJ, Stubbs Jr. EB. Experimental diabetes attenuates cerebral cortical-evoked forelimb motor responses. Diabetes 2005:54;2764-2771.
• 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. J. Neurochem. 2002;83:592-600.
• Pardue MT, Stubbs Jr. EB, Perlman JI, Narfstrom K, Chow AY, and Peachey NS. Subretinal implantation of semiconductor-based photodiodes. Immunohistochemical analysis of the retina following long-term implantation. Exp. Eye Res. 2001;73:333-343.