Targeting neuroinflammation for disease modification in models of parkinsonism
| dc.contributor.author | Hammond, Sean L., author | |
| dc.contributor.author | Tjalkens, Ronald, advisor | |
| dc.contributor.author | Legare, Marie, committee member | |
| dc.contributor.author | Bouma, Gerrit, committee member | |
| dc.contributor.author | Garrity, Deborah, committee member | |
| dc.date.accessioned | 2018-06-12T16:14:00Z | |
| dc.date.available | 2019-06-07T16:14:00Z | |
| dc.date.issued | 2018 | |
| dc.description.abstract | Chronic inflammation of the central nervous system (CNS) is a large contributing factor to neurodegeneration. Neuroinflammation is mediated by cellular communication between microglia, astrocytes, neurons and invading leukocytes from the periphery in response to neuronal injury. The second most common neurodegenerative disorder, Parkinson's disease (PD), is characterized by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and sustained neuroinflammatory activation of glial cells in the vicinity of these neurons. One master regulator of glial cell activation is transcription factor, NF-κB. NF-κB is ubiquitously expressed throughout the CNS and when activated, positively regulates neuroinflammatory genes in glia and induces prosurvival/synaptic plasticity genes in neurons. Therefore, targeting cell-specific NF-κB is critical for a desirable outcome when intervening with PD pathology. In the present studies, we utilized several experimental strategies to target neuroinflammation in multiple animal models of parkinsonism. The first utilized an astrocyte-specific NF-κB knock-out (KO) mouse model. We showed that KO animals were protected from neurotoxin-induced PD pathology and associated behavior, thus supporting the importance of astrocyte- NF-κB activation in parkinsonism. The second experimental strategy utilized small molecular compound, C-DIM12, which has agonistic properties with orphan nuclear receptor Nurr1 (NR4A2). Nurr1 activation indirectly suppresses NF-κB regulated gene expression in glial cells and also positively regulates genes associated with the production/release of DA in neurons. Through counter-regulation of NF-κB by Nurr1 activation with orally delivered C-DIM12, a neuroprotective effect was conveyed to the SN in a similar experimental mouse model of PD. Lastly, an alternative approach to modulating neuroinflammation utilized adeno-associated viruses (AAVs) to target specific cells of the CNS for transgene expression. Data revealed multiple AAV serotypes differed in transduction capacity and by comparison, an optimal serotype was identified for astrocyte targeting. Using AAV technology, transgene Nurr1 was overexpressed in astrocytes in vitro and in vivo. The preliminary results with AAV-Nurr1 display a protective effect against neurotoxicity and a promising direction for future studies. In conclusion, these studies investigate the role of neuroinflammation in relation to DA neuronal injury and provide disease modification strategies by cell-specifically targeting NF-κB and Nurr1 signaling pathways. | |
| dc.format.medium | born digital | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier | Hammond_colostate_0053A_14711.pdf | |
| dc.identifier.uri | https://hdl.handle.net/10217/189334 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation.ispartof | 2000-2019 | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.subject | dopamine | |
| dc.subject | neuroinflammation | |
| dc.subject | Parkinson's | |
| dc.subject | microglia | |
| dc.subject | astrocytes | |
| dc.subject | neurons | |
| dc.title | Targeting neuroinflammation for disease modification in models of parkinsonism | |
| dc.type | Text | |
| dcterms.embargo.expires | 2019-06-07 | |
| dcterms.embargo.terms | 2019-06-07 | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Cell and Molecular Biology | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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