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THE ROLE of TP63 in the PATHOPHYSIOLOGY of ANKYLOBLEPHARON ECTODERMAL DYSPLASIA and CLEFTING by JASON DANIEL DINELLA B.S., Geor

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THE ROLE of TP63 in the PATHOPHYSIOLOGY of ANKYLOBLEPHARON ECTODERMAL DYSPLASIA and CLEFTING by JASON DANIEL DINELLA B.S., Geor THE ROLE OF TP63 IN THE PATHOPHYSIOLOGY OF ANKYLOBLEPHARON ECTODERMAL DYSPLASIA AND CLEFTING by JASON DANIEL DINELLA B.S., George Mason University, 2002 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Cell Biology, Stem Cells and Development Program 2017 This thesis for the Doctor of Philosophy degree by Jason Daniel Dinella has been approved for the Cell Biology, Stem Cells and Development Program by Maranke Koster, Chair Peter Koch, Advisor Tom Evans Rytis Prekeris Xiao-Jing Wang Kirk Hansen Anna Bruckner Date: December 15, 2017 ii Dinella, Jason Daniel Ph.D., Cell Biology, Stem Cells and Development The Role of TP63 in the Pathophysiology of Ankyloblepharon Ectodermal Dysplasia and Clefting Thesis directed by Professor Peter J. Koch ABSTRACT Ankyloblepharon ectodermal dysplasia and clefting (AEC) is a rare autosomal dominant disorder caused by heterozygous mutations in the TP63 gene. TP63 encodes several transcription factors required for normal development and maintenance of the epidermis and its derivatives. This critical role of TP63 is underscored by abnormal development of ectodermal lineage tissues and structures including the hair, teeth, nails, and sweat glands. Patients are also often born with craniofacial clefting and partially fused eyelids. Perhaps the most striking aspect of the disorder is the associated skin erosion, which can present a potentially life-threatening circumstance to newborns and infants with the disorder. Currently, there is no cure. Patient data suggest that impaired TP63 function leads to defects in epidermal keratinocyte proliferation, differentiation, and adhesion. However, the molecular mechanisms by which TP63-AEC mutations affect these processes are not known. We posit that these defects could be key contributing factors to the skin erosions associated with AEC. Using induced pluripotent stem cell (iPSC) technology coupled with recently established gene-editing techniques, we developed a platform upon which the regulatory and functional defects associated with AEC can be observed. iPSCs were generated from two healthy donors and four AEC patients carrying different TP63-AEC mutations. Gene correction was performed for three of the iPSC lines using TALENs and CRISPRs to generate conisogenic, complement iPSC lines to facilitate the identification of AEC- associated defects. All three pairs of patient and gene-corrected iPSC lines were iii differentiated into keratinocytes. Initial transcriptome and protein analyses identified a number of genes involving cell adhesion as well as extracellular matrix deposition which were downregulated in patient iPSC-derived keratinocytes. The work presented here provides evidence that TP63-AEC keratinocytes suffer a deficiency in adhesive strength and mechanical resistance as a result of decreased expression of cell-cell and cell-extracellular adhesion genes, and changes in desmosome and hemidesmosome signaling. These results provide the basis for further functional analysis which can be performed with tissue generated from the model developed in this work, yielding greater insight into the pathophysiology underlying AEC. The form and content of this abstract are approved. I recommend its publication. Approved: Peter J. Koch iv ACKNOWLEDGEMENTS First, I would like to thank the members of the CSD community, and our former and current directors, Dr. Linda Barlow and Dr. Bruce Appel. Linda and Bruce have shown genuine interest and support towards the students in our program, and I cannot imagine it would be what it is today without their vision and guidance. Their enthusiasm for science has inspired me to take an interest in areas of developmental and cell biology outside of my own, and has motivated me to conduct more mechanistic and hypothesis-driven research. I have felt fortunate to be under their direction, and I appreciate their dedication to the program and the students, and I know others do as well. I would like to acknowledge my fellow students, as I have been consistently impressed with the level of talent and professionalism demonstrated in their research and presentations, and I am truly honored and feel privileged to have been counted among them for these past years. Being in the Dermatology department on the 8th floor in RC1-North, I was separated from our main contingent. When Senthil Lakshmana Chetty joined Dr. Maranke Koster’s laboratory adjacent to ours, I finally had another CSD student next door. Senthil has always been good to talk to, to bounce ideas off of, or to share a laugh. While more often than not, Senthil was laughing at me rather than with me, it was great having another student to work alongside. Senthil has become a dear friend, and my time here at UCD was made better through his friendship and camaraderie. The other members of Maranke’s, as well as members of Dr. Dennis Roop’s laboratories have also kindly offered their advice and assistance over these past years and I want to thank them all for their help. In particular, Charles Wall in Dennis’s lab has been a dependable floor manager who has on every occasion ensured that my needs were addressed regarding any equipment, reagents, software, or facilities and operational issues. He has also been a good state resource for me as it was through talks with Charlie that I v have become familiar with some of the finest backcountry camping and trout fishing havens in Colorado. I am fortunate also to call him a friend. In our lab, Saiphone Webb, in particular, has been a lifesaver on more than one occasion, rescuing me with backup cell cultures and experiments which have aided the progress of this work. She has been a joy in the lab, and a true asset to our team. Also from our lab, I thank Dr. Jiangli Chen. I worked more closely with Jiangli than with anyone else over these past years. I have learned a great deal under his tutelage, and indeed, much of what I now know about molecular biology can be attributed to him. He has also contributed to the work described in this thesis to include some of the Western blots I have presented, and also with the CRISPR-mediated gene-correction for two of our AEC patient iPSC lines. I’d also like to thank the members of my Thesis Advisory Committee for accepting to take part, and for freeing up time from busy schedules to meet as a group. I appreciate all the attention and enthusiasm, as well as the advice and comments which have been given regarding my project. Also, a special thanks to Dr. Anna Bruckner at Children’s Hospital, for allowing me the opportunity to visit and interact with patients. This was a meaningful experience as it really did bring the work we do in the laboratory into perspective. Also, I would like to give a very special thank you to Dr. Maranke Koster, Chair of my committee. Maranke has been an invaluable resource for me over the past years, especially regarding anything TP63. She has set my mind at ease and offered clarity and guidance countless times, and her positive nature has always been rejuvenating. Maranke really has been an inspiration for me, and I see her as my mentor as well in many ways. Also, Maranke has my thanks for sharing her translation skills during lab meetings. Absolutely invaluable. Also invaluable to me is my family. I want to give a great thanks to my sister whom I love, all of my aunts, uncles, and cousins, and my friends for their patience and support, and for not letting me go full hermit through these years. I’ll never forget when one of my cousins asked me, “so, when are you gonna graduate?” Another interjected with, “you’re not vi supposed to ask Ph.D. students that.” I am excited to be able to finally let them know there is an answer to that question now. My mother and father, to whom I owe everything, have supported me and my decisions through this entire course. They have given me strength and positivity through good times, and some of the more difficult ones. Without them, I don’t think I would have been able to achieve any of what I have. Then again, it has always been important for me to make them proud of their son. So, I more than likely would still have tried. I just would have been a lot thinner for it, and probably without gas in the car. To my Mom and Dad, I love you both, and I thank you for all the love and support you have given me. And lastly, I wish to give my thanks and appreciation to my advisor and mentor, Dr. Peter Koch, to whom I owe the greatest debt of gratitude. I would like to thank Peter for accepting me as a student in his lab and allowing me to pursue a project and a direction that I feel very passionate about, and one that was to be no small feat. At times it did present great challenges. Peter has kept faith in me during those times when I most needed encouragement and reassurance. And I want to thank him for the unending support he has provided through my progress, and my failures, each step of the way. He even complimented me once, I think. Peter has taught me that I don’t have to “reinvent the wheel” every time I start an experiment. But then he also taught me that kits are for kids. I still like to use my kits, but through working with Peter, I have learned to think more critically about my data, and to focus my efforts towards designing more meaningful experiments. It will not be within any short amount of time that the words, “you have to think like a scientist,” or, “never assume anything”, will leave my memory, and I hope they never do.
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