Mechanisms of Axonal Degeneration and Repair in a Preclinical Viral Model of Multiple Sclerosis

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Publication Type dissertation
School or College College of Engineering
Department Bioengineering
Author Yandamuri, Soumya Sathya
Title Mechanisms of Axonal Degeneration and Repair in a Preclinical Viral Model of Multiple Sclerosis
Date 2018
Description Intracranial inoculation of susceptible mice with the JHM strain of mouse hepatitis virus (JHMV) results in acute and chronic encephalomyelitis and demyelinating disease; thus, it has been used as a model of multiple sclerosis (MS). No cure currently exists for patients with MS. Recently, it has been found that increasing disability in MS is correlated with axonal damage. Remyelination is a potential method to promote axonal regeneration. We have previously shown that GFP-tagged neural precursor cells (GFP-NPCs) transplanted into the spinal cords of animals infected with JHMV reach out to damaged axons, myelinate them, and recover axonal integrity. Therefore, we sought to investigate the mechanism initiating engagement between GFP-NPCs and axons. The cell adhesion molecule, VCAM-1 is upregulated on GFP-NPCs treated with proinflammatory cytokines. Transplantation of VCAM-1 ablated GFP-NPCs using CRISPR resulted in a lack of migration or survival in vivo. Similarly, these VCAM-1 knock-out GFP-NPCs did not survive differentiation procedures in vitro. RNA sequencing of wild-type and VCAM-1 knock-out GFP-NPCs under differentiation protocols revealed a down-regulation of the Wnt signaling pathway in the knock-outs. This suggests that VCAM-1 engagement by GFP-NPCs mediates differentiation via the Wnt signaling pathway. Therefore, targeting the Wnt signaling pathway may be a method to increase remyelination and thus, maintain or promote axonal integrity. Targeting specific cell types that cause axonal damage may be another method to mitigate axonal damage. We have found that axonal damage occurs early after JHMV infection and in the absence of the adaptive immune response. Colony-stimulating factor 1 receptor (CSF1R) inhibitors PLX3397 and PLX5622 deplete microglia in the central nervous system (CNS) of JHMV infected animals. Microglia depletion results in increased demyelination, viral titers, clinical scores, and mortality; however, it also results in increased maintenance of axonal integrity. Therefore, while microglia protect animals from mortality from JHMV infection, they also may cause damage to axons at the same time. Identifying and targeting the specific factors or pathways associated with microglia that are causing axonal damage without depleting them may allow for microglia to provide protection while preventing axonopathy.
Type Text
Publisher University of Utah
Subject Biomedical engineering; Neurosciences; Immunology
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Soumya Sathya Yandamuri
Format Medium application/pdf
ARK ark:/87278/s60p68j5
Setname ir_etd
Date Created 2020-04-21
Date Modified 2021-05-06
ID 1542179
Reference URL
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