The primary focus of my research is on determining the mechanism of cell death in neurodegenerative diseases. The neurodegenerative diseases, Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS) are all similar in that the disease is usually caused by a combination of genetic predisposition and environmental factors. However, what those environmental factors are is completely unknown. We use cell culture methods to study the mechanism of toxicity of a number of potential candidates, including mercury, pesticides, and BMAA. BMAA is a non-protein amino acid that was first implicated in neurodegenerative diseases on the pacific island of Guam, but recent evidence suggests that it may be involved in triggering the onset of neurodegenerative diseases throughout the world. We have found that BMAA acts through the cystine/glutamate transporter (system xc-) to cause neuronal death. The goal of the research is to determine how environmental toxins interact with genetic predisposition, particularly at the level of system xc-, to cause neurodegenerative diseases.

A second area of interest is the toxicity of dental materials. When dental pulp cells are exposed to the environment, whether it is due to trauma, rapidly progressing cavities, or overly aggressive restoration procedures, vital pulp therapy is required to attempt to prevent the death of those cells. If this procedure fails, a root canal procedure will be required in the future. During vital pulp therapy a pulp capping material is used. The objective of the pulp capping material is to stimulate the formation of a dentin bridge over the exposed pulp. Calcium hydroxide containing materials are widely used for pulp capping because of their ability to stimulate reparative dentin formation. Reports of the success rate of pulp capping treatments vary greatly and it is clear that in actual dental practice current procedures are not always effective. A potential alternative, or adjunct, to calcium hydroxide compounds is the use of growth factors during pulp capping procedures. Growth factors have been shown to induce the formation of reparative dentine and we have shown that they can protect dental pulp cells against toxicity induced by a number of insults. Importantly, we found that the protective effects of growth factors are due to their ability to upregulate system xc-. The hypothesis being tested is that alterations in system xc- function is a determining factor in the success of pulp capping materials. The information obtained from these studies will provide guidance to determining the most effective pulp capping material to prevent the need for root-canal procedures.

Selected Publications

• Liu XQ, Albano R, Lobner D. FGF-2 induces neuronal death through upregulation of system xc-. Brain Res. 2014;1547:25-33.
• Albano R, Liu XQ, Lobner D. Regulation of system xc- in the SOD1-G93A mouse model of ALS. Exper Neurol. 2013;250:69-73.
• Bridges R, Lutgen V, Lobner D, Baker DA. Thinking outside the cleft to understand synaptic activity: contribution of the cystine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling. Pharmacol Rev. 2012;64:780-802.
• Rush T, Liu XQ, Nowakowski AB, Petering DH, Lobner D. Glutathione-mediated neuroprotection against methylmercury neurotoxicity in cortical culture is dependent on MRP1. Neurotoxicology. 2012;33:476-481.
• Rush T, Liu XQ, Lobner D. Synergistic toxicity of the environmental neurotoxins methylmercury and b-N-methylamino-L-alanine. Neuroreport. 2012;23:216-219.
• Liu X, Resch J, Rush T, Lobner D. Functional upregulation of system xc- by fibroblast growth factor-2. Neuropharmacology. 2012;62:901-906.
• Pauly K, Fritz K, Furey A, Lobner D. Insulin-like growth factor 1 and transforming growth factor-b stimulate cystine/glutamate exchange activity in dental pulp cells. J Endo. 2011;37:943-947.
• Furey A, Hjelmhaug J, Lobner D. Flow Line, Durafill VS, and Dycal toxicity to dental pulp cells:effects of growth factors. J Endo. 2010;36:1149-1153.
• Slotkin TA, Lobner D, Seidler FJ. Transcriptional profiles of glutamate transporters reveal differences between organophosphates but similarities with unrelated neurotoxicants. Brain Res Bull. 2010;83:76-83.
• Rush T, Liu X, Hjelmhaug J, Lobner D. Mechanisms of chlorpyrifos and diazinon induced neurotoxicity in cortical culture. Neuroscience. 2010;166:899-906.
• Madayag A, Kau K, Lobner D, Mantsch J, Baker D. Drug-Induced Plasticity Contributing to Heightened Relapse Susceptibility: Neurochemical Changes & Augmented Reinstatement in High-Intake Rats. J Neurosci. 2010;30:210-217.
• Liu X, Rush T, Ciske J, Lobner D. Selective death of cholinergic neurons induced by β-methylamino-L-alanine. Neuroreport. 2010;21:55-58.
• Rush T, Hjelmhaug J, Lobner D. Effects of chelators on mercury, iron, and lead neurotoxicity in cortical culture. Neurotox. 2009; 30:47-51.
• Liu X, Rush T, Zapata J, Lobner D. beta-N-methylamino-L-alanine induces oxidative stress and glutamate release through action on system Xc(-). Exp Neurol. 2009;217:429-433.