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- 저자 : Pourshafie, Naemeh (검색결과 1 건)
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Pourshafie, Naemeh ProQuest Dissertations & Theses The George Washing 2020 해외박사(DDOD)
Expanded polyglutamine tracts cause nine neurodegenerative disorders, including spinal and bulbar muscular atrophy (SBMA). In SBMA, the polyglutamine expansion occurs in the androgen receptor (AR), a ligand-dependent transcription factor. Transcriptional dysregulation and mitochondrial impairment have been implicated in these polyglutamine diseases and many other neurodegenerative disorders. In this dissertation, we genetically engineered patient induced pluripotent stem cells (iPSCs) with a doxycycline-inducible cassette containing human NGN2/ISL1/LHX3 genes. Using this model system, we investigated two types of AR-dependent transcriptional dysregulation in SBMA and their link to mitochondrial impairment. In the first study, we show that reducing mutant AR expression using a microRNA-based approach in both motor neurons and the skeletal muscle rescues the neuromuscular phenotype in SBMA adult mice. The potential to improve disease manifestations after the disease onset, suggests that the defective molecular processes can be reversed. In the next study, we found that the mutant AR co-precipitates with regions of the DNA that have no androgen response elements and is associated with overexpression of genes that are not canonical AR targets. This is consistent with an indirect role of the mutant AR in the dysregulation of gene expression. We further investigated the effect of one of the overexpressed genes, synaptojanin binding protein 2 (SYNJ2BP), an outer mitochondrial membrane protein, in SBMA cells. We show that overexpression of SYNJ2BP correlates with altered mitochondrial distribution. Also, reducing SYNJ2BP expression in SBMA motor neuron-like cells improves mitochondrial respiratory function. Our findings highlight the important role of mitochondria and energy metabolism in motor neuron health.In the final study, we found that transcriptional dysregulation in SBMA can occur through AR-mediated histone modification. In this chapter, we show reduced histone acetylation in the SBMA iPSC-derived motor neurons, resulting in low expression of metabolic genes and disruption of pathways involved in the regulation of cellular energy hemostasis. Furthermore, we provide evidence that pharmacological enhancement of mitochondrial metabolism improves motor neuron survival in SBMA.Overall, this dissertation shows the involvement of multiple cellular pathways in SBMA motor neuron degeneration and highlights different routes of intervention that can be applied to ameliorate disease manifestations in SBMA patients.
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