The scientific objective of this project is to develop a comprehensive quantitative framework of ALS from which initiation/progression can be examined and combination treatments be quantitatively generated, predicted, and prioritized. We hypothesize that there exists a pathophysiological spectrum of interactions that can only be viewed when physiology and pathology are examined together, and it is this set of interactions that holds the key to unlocking both our understanding of ALS and especially its treatment with synergistic, interaction-exploiting combination treatments. Our approach is to integrate the wealth of information derived from the ALS and related physiological literature, in conjunction with traditional experimental and clinical observations, to develop a comprehensive framework of ALS-relevant motoneuron pathophysiology using our innovative """"""""dynamic meta-analysis"""""""" technique, referred to as relational modeling. The significance of this proposal is that it will generate new and exciting ALS insight and treatment strategies in a high-throughput manner not possible with traditional experimentation alone.
The research aims consist of developing a quantitative framework of ALS using both the literature and clinical data analysis (aim 1);assess the effects of riluzole on in vivo electrophysiology (aim 2);and generating and quantitatively assessing combination treatment strategies within the developed framework (aim 3). The primary scientific outcomes of this proposal include a comprehensive model of ALS motoneuron pathophysiology, mechanistic insight into the actions of riluzole and a prioritized list of potential therapeutic strategies. The career development outcomes of this proposal include hands-on training in in vivo neuroelectrophysiology, clinical data analysis, and their integration with theory to make clinically relevant predictions.

Public Health Relevance

In this project, we use an innovative method, our form of """"""""dynamic meta-analysis"""""""" referred to as relational modeling that integrates theory, experimental, and clinical data analysis to create a quantitative framework of ALS from which clinically relevant predictions can be made regarding pathology progression. Using this developed framework, we will generate and quantitatively assess novel ALS treatments, both singly and in combination. The scientific outcome of this proposal is a prioritized list of ALS therapeutic strategies, with the career development outcomes being hands-on training in traditional neuroelectrophysiology and clinical neurodegenerative assessment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01NS069616-04
Application #
8653996
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Chen, Daofen
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Hollinger, Sabrina K; Okosun, Ike S; Mitchell, Cassie S (2016) Antecedent Disease and Amyotrophic Lateral Sclerosis: What Is Protecting Whom? Front Neurol 7:47
Jeyachandran, Amilia; Mertens, Benjamin; McKissick, Eric A et al. (2015) Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression. Front Cell Neurosci 9:462
Lee, Robert H; Mitchell, Cassie S (2015) Axonal transport cargo motor count versus average transport velocity: is fast versus slow transport really single versus multiple motor transport? J Theor Biol 370:39-44
Kim, Renaid B; Irvin, Cameron W; Tilva, Keval R et al. (2015) State of the field: An informatics-based systematic review of the SOD1-G93A amyotrophic lateral sclerosis transgenic mouse model. Amyotroph Lateral Scler Frontotemporal Degener 17:1-14
Coan, Grant; Mitchell, Cassie S (2015) An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies. Neurodegener Dis 15:301-12
Mitchell, Cassie S; Cates, Ashlyn; Kim, Renaid B et al. (2015) Undergraduate Biocuration: Developing Tomorrow's Researchers While Mining Today's Data. J Undergrad Neurosci Educ 14:A56-65
Mitchell, Cassie S; Hollinger, Sabrina K; Goswami, Shivani D et al. (2015) Antecedent Disease is Less Prevalent in Amyotrophic Lateral Sclerosis. Neurodegener Dis 15:109-13
Pfohl, Stephen R; Halicek, Martin T; Mitchell, Cassie S (2015) Characterization of the Contribution of Genetic Background and Gender to Disease Progression in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis: A Meta-Analysis. J Neuromuscul Dis 2:137-150
Foley, Avery M; Ammar, Zeena M; Lee, Robert H et al. (2015) Systematic review of the relationship between amyloid-β levels and measures of transgenic mouse cognitive deficit in Alzheimer's disease. J Alzheimers Dis 44:787-95
Irvin, Cameron W; Kim, Renaid B; Mitchell, Cassie S (2015) Seeking homeostasis: temporal trends in respiration, oxidation, and calcium in SOD1 G93A Amyotrophic Lateral Sclerosis mice. Front Cell Neurosci 9:248

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