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Rescuing TTC7A Mutant Phenotypes Associated with Very Early Onset Inflammatory Bowel Disease Via High Throughput Drug Screening

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Rescuing TTC7A Mutant Phenotypes Associated with Very Early Onset Inflammatory Bowel Disease Via High Throughput Drug Screening Rescuing TTC7A mutant phenotypes associated with Very Early Onset Inflammatory Bowel Disease via high throughput drug screening by Sasha Lee Jardine A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Biochemistry University of Toronto © Copyright by Sasha Lee Jardine 2018 Rescuing TTC7A mutant phenotypes associated with Very Early Onset Inflammatory Bowel Disease via high throughput drug screening Sasha Lee Jardine Master of Science Department of Biochemistry University of Toronto 2018 Abstract Mutations in tetratricopeptide repeat domain 7A (TTC7A) cause a severe form of Very Early Onset Inflammatory Bowel Disease (VEOIBD). Since 2013, >52 patients were reported with TTC7A- deficiency, having poor survival outcomes with combined primary immunodeficiency and severe intestinal phenotypes, including apoptotic enterocolitis and multiple intestinal atresia. Human TTC7A-knockout cells demonstrated abnormal phenotypes related to morphology and apoptosis. ttc7a-mutant zebrafish displayed abberant intestinal features, recapitulating patient disease features and establishing a novel model system for TTC7A and VEOIBD. A high-throughput drug screen identified FDA-approved drugs that rescued the apoptotic phenotype in the knockout cells. Hits of interest were further validated with orthogonal cell and zebrafish phenotypes. Our lead compound, a drug used to treat inflammatory diseases, was identified as a novel therapy to rescue TTC7A- deficiency phenotypes. Since there is no treatment option for TTC7A-deficiency and the pathobiology remains unclear, target-agnostic phenotypic drug discovery was an efficient strategy to identify novel therapeutics. ii Acknowledgments Children and families affected by TTC7A-deficiency- Thank you for your involvement in past and present endeavors to understand the nature of the disease affecting your lives. Your participation is contributing to a future where precision medicine may become a reality. Aleixo- I wanted to pursue a Masters so that I could gain more real-world experience in research. Thank you for the opportunity to “do” science and the independence to direct this project. Your research and my time in the lab has changed me and my perspectives on science, and I can’t wait to share my experiences with my students. The Muise Lab research is impactful and I’m so appreciative to have had the opportunity be a part of something that could make a difference in someone else’s life. James Dowling and Roman Melnyk- Thank you for your continued support and insights. All advice was on-point and really helped to guide this project. Roman, your drug discovery class was a game changer, it confirmed what I should be doing and made me aware of things I had not considered in drug discovery. James, I attended one of your talks and your insights on drug repurposing and rare diseases resonated with me early on in this project and solidified the rationale for much of this work. Hui- Thank you for always encouraging me to “try it”. Your positive attitude, supportive words, and expertise were inspiring. I hope that I can guide others in the way you guide all the students that come through the lab. Gaby- Thank you for always listening, troubleshooting, and teaching me how to work with zebrafish. You’ve been a critical source of guidance and a wonderful mentor. Khalid- The learning curve was steep when I came into this Masters. You were the best teacher I could have hoped for. Your patience, thoughtfulness, thoroughness and high standards for quality were always in the back of my mind throughout these years. Thank you. Neil- Thank you for the continued support, thoughtful feedback, and fantastic advice. I’ll never forget how you helped me to troubleshoot through those initial pilot screening issues. iii Neel- You have always been so generous with your time and willing to help with anything (i.e. lysing 20 plates under time and temperature sensitive conditions!). Thank you for teaching me about TTC7A, it was nice brainstorming with someone who was also invested in TTC7A. Muise Lab, Past and Present Members- Jie, Karoline, Takashi, Ryan, Cornelia, Maggie, Vritika, Zuhra, Eileen, Alessia, Neda, Qi, Frozan, Lin, and Emily. They say that it’s the combination of the work and people that make for a good graduate school experience. Thank you for your wisdom, creating a supportive atmosphere, and all the fun times. Gnocchi forever. Mark Jen, Jenny Wang, Adrian Pasculescu and Alessandro Datti- Your expertise, insights, and commitment stand out in my mind. Thank you for your help in developing the drug screen and seeing it through to the validation stages. Emily Yu, Emanuela Pannia, Ramil Noche and the Zebrafish Core Facility- Thank you for your thoughtfulness and diligence in caring for our fish and this project. Working with the zebrafish facility aided in the efficiency of experiments and helped to push this project further along. Melanie Peralta and UHN Pathology- Thank you for your professionalism and patience in working with our teenie-tiny-almost-invisible zebrafish. DPCDSB and St. Marguerite d’Youville SS colleagues- Thank you for giving me the unprecedented time-off to pursue a Master’s degree. I hope that this Masters provides further insights into the world of research for our budding scientists. My family- The last 2 years have been a little bit of a balancing act. Tom, not only you have been contributing to more than your share of the parenting, but you were always there with encouraging words. I could not have done this without your support. Ben and Frances, thank you for being silly. Mom, throughout my life you have always told me that I could do whatever I wanted, thank you for instilling confidence in me. You are so thoughtful and always willing to lend a helping hand, you kept us afloat during these years. My wonderful family, thank you for your patience and support in allowing me to pursue one of my dreams. Thank you to the CIHR, Helmsley Charitable Trust, The Hospital for Sick Children, and the University of Toronto for supporting this research. iv Table of Contents Acknowledgments.......................................................................................................................... iii Table of Contents .............................................................................................................................v List of Tables ............................................................................................................................... viii List of Figures ................................................................................................................................ ix Abbreviations ................................................................................................................................. xi List of Appendices ....................................................................................................................... xvi Epigraph ...................................................................................................................................... xvii Chapter 1 Introduction .....................................................................................................................1 1.1 Normal intestinal physiology and function ..........................................................................2 1.1.1 Tissues and cells of the GI tract ...............................................................................3 1.2 IBD .......................................................................................................................................7 1.2.1 Features of UC and CD ............................................................................................7 1.2.2 Genetic involvement in IBD ....................................................................................9 1.2.3 Environmental triggers in IBD...............................................................................10 1.2.4 The microbiome and IBD ......................................................................................10 1.2.5 Immune dysregulation in IBD ...............................................................................11 1.3 Treatment regimen for IBD ...............................................................................................13 1.4 VEOIBD ............................................................................................................................15 1.4.1 Genetics in VEOIBD .............................................................................................15 1.4.2 Understanding genetics in VEOIBD can inform clinical action ............................17 1.5 TTC7A ...............................................................................................................................18 1.5.1 Patient genetics, phenotypes and clinical background ...........................................18 1.5.2 Heterogeneous TTC7A disease phenotypes ..........................................................23 v 1.5.3 HSCT in IBD and efficacy in treating TTC7A-deficiency ....................................24 1.5.4 Genotype/phenotype correlations in TTC7A-deficiency .......................................25 1.5.5 Molecular biology of TTC7A ................................................................................26 1.5.6 Cell biology of TTC7A ..........................................................................................29 1.5.7 Biochemistry of TTC7A ........................................................................................33
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