Year: 2017
Type: article
Abstract: The cuprizone intoxication model of demyelination and remyelination has long been used to test myelin regenerative therapies for neurodegenerative diseases such as multiple sclerosis.Mice develop reversible and region-specific oligodendrocytosis and demyelination when fed this small molecule copper chelator.While the histopathology of the model has been well documented, to date, there is no consensus on cuprizone's cellular mechanism of action, and whether it involves the chelation of copper in vivo.Additionally, a variant model has been employed that combines rapamycin with cuprizone, causing more robust demyelination.In this model, rapamycin is hypothesized to suspend oligodendrocyte differentiation via the disruption of mTOR.In this work, the spatial and temporal effects of cuprizone were extensively studied in the in vivo model, and compared to a newly developed in vitro model.Global metabolomic and lipidomic profiling were utilized as analytic tools to determine biochemical pathways altered by cuprizone, rapamycin, or cuprizone and rapamycin treatments.Furthermore, oligodendrocyte differentiation in relation to mTOR was explored with transcriptomics.Together this work utilizes OMICS technology paired with analytical techniques to investigate both the chemical nature of cuprizone and the biological function of the oligodendrocyte, gaining insight into the molecular interplay that occurs during the processes of demyelination and remyelination.iv DEDICATION "Isn't nice to know a lot?And a little bit not."-Stephen Sondheim (I Know Things Now, Into the Woods) v ACKNOWLEDGMENTS The whole of this research has taken me on a long journey, starting in a seemingly empty lab as a one initial graduate student, and culminating in a group that has almost tripled.The lab has so much support and is filled with exciting energy, all in pursuit of many different scientific hypotheses.I was honored to start my academic path alongside my advisor and mentor Dr. Leah Shriver, who has instilled in me an extensive and diverse amount of knowledge.One day I too hope to have as detailed a grasp on human metabolism as her.I also have been shaped by my wonderful fellow students and labmates He Huang, Celina Cahalane, Hannah Baumann, and Rashmi Binjawadaji that I have had the honor to work alongside in our lab.I thank you especially for your endless support, and all of the coffee and snacks we have shared.I also want to thank my immediate family, Eva, Sabrina, and Matthew, as well as all of my extended family for their encouragement throughout my academic career; I hope I've made you proud.
Author: Taraboletti, Alexandra Anna
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W6980551452