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dc.contributor.advisorHong Zhang, PhD
dc.contributor.authorNeherin, Kashfia
dc.date.accessioned2024-03-28T18:35:13Z
dc.date.available2024-03-28T18:35:13Z
dc.date.issued2024-03-06
dc.identifier.doi10.13028/96wz-xf10
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53248
dc.description.abstractInvestigation of disease-associated cellular changes in vitro has leaped forward significantly with the innovation of induced pluripotent stem cell (iPSC) technology. However, resetting the epigenetic landscape and aging clock during reprogramming results in iPSC-differentiated cells resembling fetal cell types instead of adult or aged cells. The lack of cellular aging in iPSC-based models presents a significant drawback in the investigation of age-associated diseases such as Alzheimer’s disease. My thesis aims to introduce proper cellular aging to improve iPSC-based modeling of neurodegeneration. Toward this goal, I created an inducible system to trigger senescence in iPSC-based cell models, as recent studies showed senescence playing a crucial role in aging and neurodegeneration. I utilized CRISPR-interference (CRISPRi) to suppress telomere repeat factor 2 (TERF2), a significant component of the telomere-protecting Shelterin complex. I demonstrated that suppression of TERF2 in iPSCs robustly activated DNA damage response (DDR), p53/p21 signaling, and cellular senescence in an inducible and synchronized manner. The inducible approach allows temporal control of senescence activation throughout differentiation from iPSCs to desired cell types. I applied the CRISPRi-TERF2 approach to iPSC-differentiated neural progenitor cells (NPCs) and showed that suppression of TERF2 efficiently activated DDR, p53/p21 signaling, and cellular senescence in differentiated NPCs. This inducible model of cellular senescence generated in this study will enable the investigation of cellular senescence using isogenic comparisons in the progression of age-associated neurodegeneration and improve disease modeling with a proper cellular aging context to facilitate drug discovery.en_US
dc.language.isoen_USen_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rightsCopyright © 2024 Kashfia Neherin. All Rights Reserved.en_US
dc.subjectCellular Senescenceen_US
dc.subjectiPSCen_US
dc.subjectTelomereen_US
dc.subjectDNA damageen_US
dc.subjectShelterinen_US
dc.subjectNeurodegenerationen_US
dc.titleIntroducing Telomere-Dysfunction Induced Cellular Senescence in iPSC-Based Modeling Of Neurodegenerative Diseasesen_US
dc.typeDoctoral Dissertationen_US
atmire.contributor.authoremailkashfia.neherin@umassmed.edu, KashNeherin@gmail.comen_US
dc.contributor.departmentPediatricsen_US
dc.description.thesisprogramInterdisciplinary
dc.identifier.orcid0009-0005-8783-9515


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