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High Throughput Single-Molecule Telomere Characterization and Application in Prostate Cancer
Start Date: 2/10/2017Start Time: 10:30 AM
End Date: 2/10/2017End Time: 12:30 PM

Event Description
BIOMED PhD Research Proposal

High Throughput Single-Molecule Telomere Characterization and Application in Prostate Cancer

Jennifer McCaffrey, PhD Candidate, School of Biomedical Engineering, Science and Health Systems

Ming Xiao, PhD, Associate Professor, School of Biomedical Engineering, Science and Health Systems

In humans, telomeres are a nucleoprotein complex made up of tandem 5’TTAGGG3’ repeats and associated protective proteins located at the ends of all 46 chromosomes. Telomeres prevent chromosome ends from being recognized as DNA damage which triggers of DNA end-joining, DNA recombination, or DNA repair that would lead to unstable chromosomes. Currently, there is no method that is capable of measuring all individual telomeres which has hindered telomere research. It has been shown that the shortest telomere or a portion of the shortest telomeres is critical for chromosome stability and cell viability. Therefore, it is important to measure the frequency of short telomeres to detect small changes in telomere length. Having a higher frequency of short telomeres has been related to an increased risk of different cancers. Specifically, telomere shortening is observed early in prostate cancer (PCa) where it likely drives malignant transformation and tumor progression. Preliminary studies have suggested that shorter telomere length in PCa tissue may be associated with poor clinical outcomes in patients and therefore could possibly serve as a potential molecular marker.

To address the need for a technology to measure telomere length globally, we have recently developed a method that simultaneously measures individual telomeres in a single reaction. Single-telomere-resolution will allow for unprecedented insight into the role(s) of telomere loss, telomere breakage/re-joining, and telomerase or ALT dependent telomere elongation play in carcinogenesis. This novel technology will provide a high-throughput method to better understand mechanisms of telomere length regulation and dysfunction at single-telomere resolution as well as a means to screen regions of the human genome for genetic susceptibilities to diseases.

Our method modifies the Type II CRISPR/Cas9 system and uses designed gRNAs to direct a Cas9 nickase to target specific genomic sequences in vitro. We combined the CRISPR/Cas9 nick-labeling technology with global Nt. BspQI (CGTCTTC) based nick-labeling to label telomere repeats and subtelomeric regions respectively. Preliminary results show the method efficiently labels and distinguishes subtelomeres linked to their respective telomeres of genomic DNA for nanochannel analysis. This method was applied to quantitatively analyze the change in telomere length in aging and cancer cell lines. In this study, we will optimize the method for a wide range of biological samples to demonstrate the relevance of this technology for different sample types. Additionally, we will develop the technology for comprehensive allele-specific analysis of each genomic telomere. Inhibitor experiments will be performed on a prostate cancer cell line to induce telomere dysfunction to determine the impact on haplotype-resolved telomere lengths in prostate cancer.
Contact Information:
Name: Ken Barbee
Phone: 215-895-1335
Email: barbee@drexel.edu
Jennifer McCaffrey
One Drexel Plaza, Room GL35, 3001 Market Street
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