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dc.contributor.advisorLorson, Christian L.eng
dc.contributor.authorKhairallah, Marie-Thereseeng
dc.date.issued2018eng
dc.date.submitted2018 Springeng
dc.descriptionField of study: Microbiology and immunology.eng
dc.descriptionDr. Christian L. Lorson, Dissertation Supervisor.eng
dc.descriptionIncludes vita.eng
dc.description"May 2018."eng
dc.description.abstract[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and the leading genetic cause of infant mortality. SMA is caused by afunctional loss of the survival motor neuron-1 (SMN1) gene and the subsequent deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. SMA presents by motor neuron loss and muscle atrophy, and historically was considered an autonomous disease of the a-lower motor neuron (LMN). In this work we investigated effects of low levels of SMN outside the LMNs. Specifically, we looked in the spleen to determine the impact of SMN deficiency on the spleen development and the integrity of the splenic immune cells. Additionally, we analyzed astrocytes to determine if they exhibit functional impairments that could compromise their role in supporting the survival and function of LMNs. First, we reported spleen hypoplasia in multiple SMA mouse models with alteration of the splenic architecture due to a severe reduction in the red pulp zone and relative conservation of the white pulp area. We found alterations in the relative abundance of splenic mediators of the immune response, where the resident macrophage subset was depleted starting at early pre-symptomatic time (post-natal day 2), whereas the B- and T-lymphocytes, and CD11b+ macrophages had higher frequency at the late symptomatic age (post-natal day 12). Secondly, we showed that primary astrocytes derived from the spinal cord of a SMA mouse model had compromised efficiency in their glutamate uptake capacity. Moreover, SMA spinal cords had altered expression in the level of flottilin-1, a lipid raft protein necessary for cell membrane integrity and for the function of receptors and transporters. Furthermore, we showed a higher expression of the NR2B, a subunit of the glutamate receptor NMDAR that signals mainly toward apoptosis. In summary, this work characterized new pathologies in two non-neuronal tissues in the CNS and in the periphery, demonstrated that the spleen and the immune system are likely contributing to the overall clinical pathology of SMA, and found altered mechanisms in astrocytes function that might explain their effect on LMNs in SMA.eng
dc.description.bibrefIncludes bibliographical references (pages 98-116).eng
dc.format.extent1 online resource (x, 117 pages) : illustrations (some color)eng
dc.identifier.merlinb129059845eng
dc.identifier.oclc1091630324eng
dc.identifier.urihttps://hdl.handle.net/10355/66066
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartofcollectionUniversity of Missouri--Columbia. Graduate School. Theses and Dissertationseng
dc.rightsAccess to files is limited to the University of Missouri--Columbia.eng]
dc.rightsAccess to files is limited to the University of Missouri--Columbia.eng]
dc.subject.FASTSpinal muscular atrophy.eng
dc.subject.FASTImmune systemeng
dc.subject.FASTPathophysiology.eng
dc.subject.FASTAstrocytes.eng
dc.titleContribution of the immune system and astrocytes to spinal muscular atrophy pathologyeng
dc.typeThesiseng
thesis.degree.disciplineMolecular microbiology and immunology (MU)eng
thesis.degree.grantor[University of Missouri--Columbia]eng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


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