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AAV-Ifnβ Gene Therapy for Glioblastoma: a Dissertation University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2016-07-22 A Walk on the Fine Line Between Reward and Risk: AAV-IFNβ Gene Therapy for Glioblastoma: A Dissertation Dwijit Guhasarkar University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Genetic Processes Commons, Genetics and Genomics Commons, Neoplasms Commons, and the Therapeutics Commons Repository Citation Guhasarkar D. (2016). A Walk on the Fine Line Between Reward and Risk: AAV-IFNβ Gene Therapy for Glioblastoma: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/M2B59C. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/843 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. A WALK ON THE FINE LINE BETWEEN REWARD AND RISK: AAV-IFN GENE THERAPY FOR GLIOBLASTOMA A Dissertation Presented By DWIJIT GUHASARKAR Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY July 22, 2016 INTERDISCIPLINARY GRADUATE PROGRAM A WALK ON THE FINE LINE BETWEEN REWARD AND RISK: AAV-IFN GENE THERAPY FOR GLIOBLASTOMA A Dissertation Presented By DWIJIT GUHASARKAR The signatures of the Dissertation Defense Committee signify completion and approval as to style and content of the Dissertation ____________________________________________ Miguel Sena-Esteves, Ph.D., Thesis Advisor ____________________________________________ Guangping Gao, Ph.D., Member of Committee ____________________________________________ Richard P. Moser, M.D., Member of Committee ____________________________________________ Christian Mueller, Ph.D., Member of Committee ____________________________________________ Xandra O. Breakefield, Ph.D., Member of Committee The signature of the Chair of the Committee signifies that the written dissertation meets the requirements of the Dissertation Committee ____________________________________________ Alonzo Ross, Ph.D., Chair of Committee The signature of the Dean of the Graduate School of Biomedical Sciences signifies that the student has met all graduation requirements of the school. ____________________________________________ Anthony Carruthers, Ph.D., Dean of the Graduate School of Biomedical Sciences INTERDISCIPLINARY GRADUATE PROGRAM July 22, 2016 iii Dedicated to the malignant cancer patients all over the world and their families iv Acknowledgements The sweet fruit of years of hard works, patience and perseverance, which is being consolidated today in the form of this doctoral dissertation, was not possible without the profound contributions from several people and institutions in my life. I would not have the scope to mention all the people and their valuable contributions, but today I definitely remember and appreciate all their help, support and contributions that I receieved over the years. Here I want to take the opportunity to mention at least some of them who were themselves part of the journey or were source of inspiration and the driving forces behind this journey. First of all, I want to express my sincere gratitude to my doctoral research adviser Dr. Miguel Sena-Esteves for having trust on me and giving me the great opportunity to work, learn and grow as a scientist in his laboratory. I will be grateful to him forever for everything I learned from him during my PhD career. This experience will be my invaluable asset for the rest of my life. I also greatly appreciate all his support throughout the time I spent in his laboratory especially when I needed it the most. I drove the research projects that were primarily conceptualized by Dr. Sena- Esteves. The dissertation research was executed using his laboratory resources, funding and most importantly his intellectual guidance. All my QE, TRAC and DEC members were extremely helpful. I appreciate their invaluable suggestions and precious time that helped me to accomplish this dissertation work. I greatly appreciate the contribution of Dr. Guangping Gao, Dr. Alonzo Ross, Dr. Christian Mueller, Dr. Carlos Lois, Dr. Daryl Bosco, Dr. v Lawrence Hayward and Dr. Richard P. Moser. I especially thank Dr. Xandra O. Breakefield for agreeing to be my external committee member. I want to thank Qin Su and the Vector Core at the Horae Gene Therapy Center who made AAV vectors that were used in the study. I want to thank Yu and Amanda at the morphology core at University Medical School who did some of the histological works in the study. I thank James Neiswender, who during his rotation in our lab started the project and worked for the first 2 months of the study described in Chapter II. I appreciate the service of the Animal Medicine Department at UMass Medical School for their help in animal care and maintenance. In particular I want thank Suzanne Wheeler who allowed me to use the surgery room at A-level animal facility without any extra cost. Veterinarian Nina Bishop, senior animal technician Valerie Qudsieh Mount and other animal technicians took very good care of the mice used in my studies and were extremely helpful. I also want to thank the IVIS imaging core at UMass Medical School where all the live bioluminescence imaging studies were carried out. I also greatly value the funding support provided by NIH (Grant# R01NS066310, MS-E) and internal development funding of the institution. Next, I don’t want to miss the opportunity to mention it here that I am extremely lucky to be born to a tremendously supportive family. I owe all my being to my parents (Mr. Subir Guha Sarkar and Mrs. Rita Guha Sarkar) without whose constant guidance, support and encouragement I would not be able to study this far or choose a career path of my dream. Coming from only a modest socio-economic background it was not easy for them to be supportive with my choosing to do research instead of going for more conventional and financially lucrative jobs. But their only priority was to vi fulfill my dream. Any word in the dictionary would fall short to express my feelings of gratitude and admiration towards them. And the cherry on the cake for me is my sweetest and loving younger sister (Ms. Tishya Guha Sarkar). Not only she is the best sibling one can ever imagine, she has been my friend, my source of energy and my pain relieving balm. She showed tremendous amount of mental strength and courage in taking care of my ailing parents for the last few years at home in India, even sometimes at the cost of her own study and career, so I could complete my PhD studies here in the United States without any obstacles. I am short of my vocabulary to thank her enough for all what she did. Thank you Mum, Bapi and Bonu. I also want to thank Didi (my maternal grandma) for encouraging me to pursue higher studies. After my family, a big chunk of credit for my being able to come this far goes to my teachers at all the levels of my student life. My primary school teachers are responsible to a large extent for building my character and teaching me the importance of integrity, sincerity and discipline in life. The values they instilled in young me are still the core values I carry within. Thank you Ms. Sunetra Ghosh, Ms. Nandita Ghosh, Ms. Kakali Bose, Ms. Namita Ghosh, Ms. Seema Banerjee and others. Also this was the time when I first started to experience the fun of science. Then as I moved through the middle and high school at Jodhpur Park Boys’ School I was inspired and motivated by many selfless and great teachers. Rabi-babu, Manas-babu, Dipankar-babu, Tushar-babu, Sagar-babu, Satyaranjan Das- and Satyaranjan Chakraborty-babu, Uttam-babu, Sajal-babu _all influenced my life positively. About this time I became more determined than ever that I would choose science as my stream of higher studies. But the person who made the strongest vii impression on me during this time was Mr. Arup Sengupta, the best life science teacher I have ever come across in my life. Be it in the scheduled classes, or in the unscheduled informal discussion sessions during school lunch hours or at his residence, where he gave me countless hours of free tuitions, I would get mesmerized by his teaching and persona every day. I was so impressed with his teaching technique, chalk-board work, sketch drawing in the class and his personality overall that I started idolizing him. His graduate schooling background was in physiology and so it was easy for me to decide on my choice of subject in college. Thank you Arup- babu for all your selfless helps and the inspirations! During my undergraduate study with physiology major, I was especially lucky to win motherly affections, help and career guidance from two of my teachers_ Meera Ma’am and Sukti Ma’am, whom I admire a lot. They strongly encouraged me to take up biochemistry or molecular biology as my next subject of study at the Masters level. Thanks Ma’am for your invaluable career suggestions then. My experience at the Department of Biochemistry, Calcutta University as a student of M.Sc. and later as a research scholar was a life-changing one. I probably would not have decided to do research or plan to come for a PhD program unless I got the scientific exposure I got here from both teachers and other graduate students. Also during this time I had my first exposure to a research lab during my summer research stint at Dr. Nahid Ali’s lab. Thank you Nahid Ma’am! Among several good teachers I will particularly mention the names of Dr.
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