Investigator: Edward Dougherty, Roger Williams University

Scientific Theme: Neuroscience

Abstract: The goal of this research is to construct a comprehensive mathematical model of a dopaminergic neuron that can be utilized to study the biological mechanisms by which electrical stimulation therapies treat Parkinson’s disease. The specific aims are to: (i) Develop and implement a mathematical model of a dopaminergic neuron that couples transmembrane electrodynamics with intracellular signaling pathways and species associated with Parkinson’s disease progression, and (ii) Identify the impact of a neurostimulation based electric current on the intracellular signaling pathways and species associated with Parkinson’s disease through computational simulation. The approach will include several independent phases. First, we will complete an ordinary differential equation based mathematical model of the intracellular signaling pathway of fundamental species related to Parkinson’s disease, including the DJ-1, Parkin, Pink1, α-synuclein, and IPAS proteins, as well as calcium, all of which have been identified as key members of the pathway that regulates dopaminergic neuron gene expression and ultimately neuronal survival. Second, we will develop a higher-level, partial differential equation based neuron model that includes sodium, potassium, chloride, and calcium ion concentration distributions in both the cytosolic and extracellular domains, as well as ion flux transport through the cell membrane via voltage-gated ion channels. Then, these models will be integrated using cytosolic calcium as a fundamental regulator of the intracellular signaling pathway. Finally, a simulated electric field will be administered and computational experiments will demonstrate how the signaling pathway is influenced by neurostimulation therapies. These in silico experiments will help achieve the long-term objective of explaining the mechanisms by which neurostimulation functions, provide a tool to augment biological experimentation, and uncover potential pharmaceutical targets for treating the progression of Parkinson’s disease.

Human Health Relevance:  Parkinson’s disease (PD) affects approximately one million individuals in the United States alone, and currently there is no cure. While treatments for PD have shown some success in alleviating symptoms of this disease, it is unknown HOW these treatments work. Our goal is to use computer-based models and mathematical approaches to study PD and its treatments at the cell level to gain insight into how PD treatments work. These results will expand the understanding of PD progression, and help in the discovery new methods for treating Parkinson’s disease.