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Title page for ETD etd-09162017-134651

Type of Document Dissertation
Author Armstrong, Laura Craig
URN etd-09162017-134651
Title Modeling Tuberous Sclerosis Complex Using Patient-Derived Cells
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Kevin Ess Committee Chair
Aaron Bowman Committee Member
Andrea Page McCaw Committee Member
Charles Hong Committee Member
David Miller Committee Member
  • p53
  • induced pluripotent stem cells
  • tuberous sclerosis complex
  • mTOR
Date of Defense 2017-08-11
Availability unrestricted
Tuberous Sclerosis Complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity. TSC causes refractory epilepsy and intellectual disability but the pathogenesis of the neurological symptoms is not understood. Identifying when and in what cell types mutations in TSC1 or TSC2 lead to neurological dysfunction is the first step to better and more targeted treatments. To study aberrations of early development in TSC, we generated induced pluripotent stem cells using dermal fibroblasts obtained from patients with TSC. During validation, we found that stem cells generated from TSC patients had a very high rate of integration of the reprograming plasmid containing a shRNA against TP53. Loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53 levels and impair stem cell reprogramming. Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene dosage. Further, we show that homozygous loss of TSC2 leads to increased mTORC1 in neural progenitors and impaired neural progenitor formation. These results support the contributions of TSC2 heterozygous and homozygous mutant cells to the pathogenesis of TSC and the important role of p53 during reprogramming.
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