Victoria Jimenez
Victoria Jimenez
Victoria Jimenez
Helios Scholar
School: University of Southern California
Hometown: Phoenix, Arizona
Daily Mentor: Noelle Fukushima
PI: Floris Barthel, MD

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Investigating somatic variations and mutations in normal human astrocytes with artificially induced telomere dysfunction

Gliomas are tumors that arise from glial cells and account for about a third of all brain tumors. While telomere dysfunction can be defined, the role it plays in gliomagenesis and how it affects tumor cells is unknown. Telomere dysfunction is a consequence of telomere shortening and causes instability through breakage-fusion-bridge (BFB) cycles, as well as end-to-end fusions. In order to examine this process, we disrupted the shelterin complex, a multi-protein complex that protects telomeres. hTERT-immortalized Normal Human Astrocytes (NHA) were transfected with TRF2ΔBΔM to induce artificial telomere dysfunction. TRF2ΔBΔM is a genetically modified dominant negative allele of TRF2 that not only changes the shelterin complex, but prevents TRF2 from binding to telomeres. We used this model to compare the transfected cells with NHA primary cells by whole genome sequencing (WGS). We hypothesize that the TRF2ΔBΔM cells will have more somatic variations, such as structural variants and copy number variations, as well as mutations. Analyzing these libraries after completing WGS, we observed more structural variants in the TRF2ΔBΔM cells than in NHA cells. Our efforts generated 8 genomes worth of sequencing data which will provide opportunities for more in-depth analysis in the future. In addition, we plan to analyze an inducible TRF2ΔBΔM mutant and spontaneous telomere dysfunction in future experimentation. Optimizing this model could facilitate identification of patterns in mutations and variations for gliomagenesis, leading to possibilities such as hTERT-targeted cancer therapy.


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