Amyotrophic lateral sclerosis (ALS) is an incurable, fatal disease characterized by selective death of fast- twitch spinal motoneurons (F-MNs) before slow-twitch spinal motoneurons (S-MNs), a degeneration differential which suggests that S-MNs are less vulnerable to ALS than F-MNs. Riluzole, the only ALS treatment, extends life by only 3 months; thus, understanding the mechanisms that prolong life in S-MNs or hasten death in F-MNs could provide targets for more effective treatments. Our previous work has shown that S- and F-MNs differ in their intrinsic expression of SK channels. As SK current contributes to MN excitability regulation, this could potentially explain the vulnerability differential between S- ad F-MNs in ALS. Understanding MN excitability dysregulation in ALS is challenging because ongoing disease and compensatory changes have opposing pro- and anti-excitability effects that maintain a pseudo-normal net excitability which masks disease progression. Because multiple changes take place concurrently, and because some changes cannot be directly measured in experiments, experimental methods require the support of computer simulations that are accurate enough to analyze the effects of individual cellular changes on overall MN excitability. Therefore, to study mechanisms underlying the vulnerability differential between S- and F-MNs in ALS, we will develop high-fidelity computational models based on in-vitro animal data. These models will be used to examine the impact of differing SK channel expression levels between S- and F-MNs. While computational models are useful, their predictions are theories which require challenge and validation by experimental tools. Therefore, we will use immunohistochemistry and electrophysiology experiments to test model predictions in transgenic mice. The data from these experiments will be used to update the computational models, in an iterative cycle, to produce a next generation of computational models with even more accurate predictions. Resulting predictions will be used to plan additional experiments to rigorously test hypotheses on the contribution of SK channels to overall disease progression in S- vs. F-MNs.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is an incurable, fatal disease characterized by weakness and paralysis, culminating in respiratory failure and death 1-3 years after symptoms appear. This proposal focuses on examining the mechanisms that underlie the differential degeneration of motoneuron types in ALS. The premise is that motoneuron types have differences in their intrinsic properties that may contribute to the disease process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091836-02
Application #
8997138
Study Section
Neuroscience and Ophthalmic Imaging Technologies Study Section (NOIT)
Program Officer
Gubitz, Amelie
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Wright State University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
047814256
City
Dayton
State
OH
Country
United States
Zip Code
45435
Dukkipati, S Shekar; Garrett, Teresa L; Elbasiouny, Sherif M (2018) The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis. J Physiol 596:1723-1745
Allen, John M; Elbasiouny, Sherif M (2018) The effects of model composition design choices on high-fidelity simulations of motoneuron recruitment and firing behaviors. J Neural Eng 15:036024
Mahrous, Amr A; Elbasiouny, Sherif M (2018) Modulation of SK channels regulates locomotor alternating bursting activity in the functionally-mature spinal cord. Channels (Austin) 12:9-14
V-Ghaffari, Babak; Kouhnavard, M; Elbasiouny, Sherif M (2017) Mixed-mode oscillations in pyramidal neurons under antiepileptic drug conditions. PLoS One 12:e0178244
Dukkipati, S Shekar; Chihi, Aouatef; Wang, Yiwen et al. (2017) Experimental Design and Data Analysis Issues Contribute to Inconsistent Results of C-Bouton Changes in Amyotrophic Lateral Sclerosis. eNeuro 4:
Elbasiouny, Sherif (2017) Cross-Disciplinary Medical Advances with Neuroengineering: Challenges Spur Development of Unique Rehabilitative and Therapeutic Interventions. IEEE Pulse 8:4-7
Mahrous, Amr A; Elbasiouny, Sherif M (2017) SK channel inhibition mediates the initiation and amplitude modulation of synchronized burst firing in the spinal cord. J Neurophysiol 118:161-175
Santin, Joseph M; Wang, Tobias; Dukkipati, Saihari S et al. (2016) Commentary: The Spinal Cord Has an Intrinsic System for the Control of pH. Front Physiol 7:513
V-Ghaffari, Babak; Kouhnavard, M; Kitajima, T (2016) BIOPHYSICAL PROPERTIES OF SUBTHRESHOLD RESONANCE OSCILLATIONS AND SUBTHRESHOLD MEMBRANE OSCILLATIONS IN NEURONS. J Biol Syst 24:561-575
Jiang, Mingchen C; Elbasiouny, Sherif M; Collins 3rd, William F et al. (2015) The transformation of synaptic to system plasticity in motor output from the sacral cord of the adult mouse. J Neurophysiol 114:1987-2004

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