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dc.contributor.advisorRobert H. Brown Jr.
dc.contributor.authorLee, Pin-Tsun Justin
dc.date2022-08-11T08:08:39.000
dc.date.accessioned2022-08-23T16:03:04Z
dc.date.available2022-08-23T16:03:04Z
dc.date.issued2021-12-21
dc.date.submitted2022-03-11
dc.identifier.doi10.13028/jg9c-nx43
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31405
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disorder that selectively affects both upper and lower motor neurons, leading to muscle weakness, paralysis and death. Despite recent advances in the identification of genes associated with ALS, the quest for a sensitive biomarker for rapid and accurate diagnosis, prognosis, and treatment response monitoring has not been fulfilled. In this thesis, I report a method of quantifying the integrity of motor neurons in vivo using imaging to record uptake and retrograde transport of intramuscularly injected tetanus toxin fragment C (TTC) into spinal motor neurons. This method tracks and profiles progression of disease (transgenic SOD1G93A and PFN1 ALS mice) and detects subclinical perturbations in net transport, as analyzed in C9orf72 transgenic mice. It also defines a progressive reduction in net transport with aging. To address whether our technique enables drug development, I evaluated therapeutic benefits of (1) gene editing and (2) mutant gene silencing (with RNAi targeting SOD1) in SOD1G93A transgenic mice by characterizing their net axonal transport profiles. I constructed a computational model to evaluate key molecular processes affected in net axonal transport in ALS mouse model. The model allows prediction of key parameters affected in a C9ORF72 BAC transgenic mouse line. Prior immunization with tetanus toxoid does not preclude use of this assay, and it can be used repetitively in the same subject. This assay of net axonal transport offers broad clinical application as a diagnostic tool for motor neuron diseases and as a biomarker for rapid detection of benefit from therapies for transport dysfunction in a range of motor neuron diseases.
dc.language.isoen_US
dc.rightsLicensed under a Creative Commons license
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectAmyotrophic lateral sclerosis
dc.subjectaxon degeneration
dc.subjectaxon transport
dc.subjectneuromuscular disease imaging
dc.subjectbiomarker
dc.subjectDiagnosis
dc.subjectDisease Modeling
dc.subjectNervous System Diseases
dc.subjectOther Analytical, Diagnostic and Therapeutic Techniques and Equipment
dc.subjectOther Neuroscience and Neurobiology
dc.titleQuantitative Imaging of Net Axonal Transport in vivo: A Biomarker for Motor Neuron Health and Disease
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2181&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/1171
dc.legacy.embargo2022-03-11T00:00:00-08:00
dc.identifier.contextkey28349560
refterms.dateFOA2022-08-24T04:01:23Z
html.description.abstract<p>Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disorder that selectively affects both upper and lower motor neurons, leading to muscle weakness, paralysis and death. Despite recent advances in the identification of genes associated with ALS, the quest for a sensitive biomarker for rapid and accurate diagnosis, prognosis, and treatment response monitoring has not been fulfilled. In this thesis, I report a method of quantifying the integrity of motor neurons in vivo using imaging to record uptake and retrograde transport of intramuscularly injected tetanus toxin fragment C (TTC) into spinal motor neurons. This method tracks and profiles progression of disease (transgenic SOD1<sup>G93A</sup> and PFN1 ALS mice) and detects subclinical perturbations in net transport, as analyzed in C9orf72 transgenic mice. It also defines a progressive reduction in net transport with aging. To address whether our technique enables drug development, I evaluated therapeutic benefits of (1) gene editing and (2) mutant gene silencing (with RNAi targeting <em>SOD1</em>) in SOD1<sup>G93A</sup> transgenic mice by characterizing their net axonal transport profiles. I constructed a computational model to evaluate key molecular processes affected in net axonal transport in ALS mouse model. The model allows prediction of key parameters affected in a <em>C9ORF72</em> BAC transgenic mouse line. Prior immunization with tetanus toxoid does not preclude use of this assay, and it can be used repetitively in the same subject. This assay of net axonal transport offers broad clinical application as a diagnostic tool for motor neuron diseases and as a biomarker for rapid detection of benefit from therapies for transport dysfunction in a range of motor neuron diseases.</p>
dc.identifier.submissionpathgsbs_diss/1171
dc.contributor.departmentDepartment of Neurology, Program in Neuroscience
dc.description.thesisprogramNeuroscience
dc.identifier.orcid0000-0002-3444-9696


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