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Development of a Lab Bioimage Informatics System for Fluorescence Microscopy Data, with Application to Experimental Studies of R

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Development of a Lab Bioimage Informatics System for Fluorescence Microscopy Data, with Application to Experimental Studies of R Development of a lab bioimage informatics system for fluorescence microscopy data, with application to experimental studies of RhoGAP regulation of calcium signaling and actomyosin contractility. A Dissertation Presented By Jeffrey Alan Bouffard to The Department of Bioengineering in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the field of Bioengineering Northeastern University Boston, Massachusetts December 2019 ii ABSTRACT Microscopic imaging is a powerful tool to advance our understanding of biological systems. Image-based biological investigations can be large and complex, requiring bioimage informatics solutions to manage and examine large amounts of information. This dissertation describes the development of a lab bioimage informatics system to organize and analyze fluorescence microscopy movies. This system is applied here to investigate the regulation of calcium signaling and actomyosin contractility in the C. elegans spermatheca, a multicellular contractile tube with stereotyped tissue function and conserved genes and regulatory networks. The lab bioimage informatics system standardizes the organization, processing, and analysis of calcium sensor movies by using computer programs to automate processes. The motivations, design goals, and implementation for this lab bioimage informatics system are presented. The experimental investigation revealed a new role for a RhoGAP known to regulate actomyosin contractility. For this work, the lab bioimage informatics system supported analysis of almost 500 fluorescence microscopy movies, acquired by 4 different people over 4 years. These data show that the RhoGAP SPV-1 is a key regulator of calcium signaling and tissue function in the C. elegans spermatheca. Experiments to establish mechanism suggest SPV-1 coordinates the activity of multiple GTPases to control tissue contractility. An additional prototype image processing and analysis pipeline is presented, which automatically segments the spermathecal tissue from calcium sensor movies. This pipeline will advance spatial analysis of the tissue, enabling quantitative analysis of tissue shape changes and mechanochemical signaling in the spermatheca. A major product of this dissertation is an operational lab bioimage informatics system, used by multiple researchers for more than two and a half years to organize iii movies and support publications and collaborations. This dissertation work also produced a biological investigation, using standardized analysis of movies, which was published in a Molecular Biology of the Cell special issue on Quantitative Cell Biology. A final product is an image processing pipeline that extracts new spatial measurements from movies. The tools and insights presented here continue to be used, and the framework presented may be useful for other researchers dealing with large amounts of complex imaging data. iv DEDICATION I dedicate this work to those with the audacity to follow their own path to the mysteries. v ACKNOWLEDGEMENTS I have many people to thank for making this achievement possible. First and foremost, none of this would have been possible without the support and guidance of my primary advisor, Professor Erin Cram. She is a paragon of great research and general humanity, and it has been a privilege and honor to do my Ph. D. work in her lab. I am the scientist, researcher, writer, and presenter I am today because of her insightful questioning and seemingly endless patience and feedback. I became a programmer and synthetic biologist only because she allowed me to develop in the ways that were best for me. I would not be the mentor and research community member I am today without her masterful example of how to support our fellow human beings in our research endeavors. Thank You, Erin! I thank Professor Jeffrey Ruberti and the Northeastern University Bioengineering Program for accepting and supporting a very non-traditional candidate, and for giving me the opportunity to radically alter the trajectory of my life. Before grad school I spent years as a waiter in a restaurant, now I command the skills and mindsets to lead in my chosen dream career, engineering biology. This experience has shown me that I am capable of so much more than I ever thought possible! I thank Professor Anand Asthagiri for helping me develop as an engineer, and for welcoming me into his group lab meetings. Insights from our conversations helped me become a better researcher, and helped me plot my career course. I thank Professor Harikrishnan Parameswaran for helping me develop as an engineer, and for providing me space and resources in his lab office. Our meetings advanced my image analysis skills, and helped me plot my career course. These years would have been a lot harder if I had not worked alongside such amazing people in the Cram Lab. I must give particular shout-outs to Ismar Kovacevic vi and Jose Orozco for showing me the ropes; Alyssa Cecchetelli and Coleman Clifford for being great collaborators; Alison Wirshing, Charlotte Kelley, and Perla Castaneda for great discussions and keeping the lab running and upbeat; and Pedro Falcon and Doug Pagani for reminding me how much I enjoy teaching others. Many more current and former members of the Cram lab are not mentioned here, but they all contributed to making it the magical place it is. Thank You, Cram Lab, I will very much miss the great science and camaraderie, the lab meetings and birthday parties, and the stimulating and supportive environment. I thank the members of the Asthagiri lab for welcoming me at their lab meetings, and the members of the Parameswaran lab for welcoming me in their office area. I thank Professor Javier Apfeld and the members of the Apfeld lab for helpful discussions at joint lab meetings. I also thank Professor Ronen Zaidel-Bar, Pei Yi Tan, and the members of the Zaidel-Bar lab for hosting me in Singapore for two months. Northeastern Bioengineering was a brand new program when I started, so I thank the people who put in time and energy to build a graduate student community from scratch, particularly Robert Natividad, Michelle Stolzoff, Jessica Fitzgerald, Paige Baldwin, Shravani Kakarla, Judith Piet, and Ian Harding. The path certainly would have been lonelier without this BioE camaraderie. I also thank the Northeastern Biology department for having and supporting a strong community that was a pleasure to be a part of. I thank two great housemates that I shared living space with over these years, Greg Spiers and Don Medor. A low-stress and drama-free living situation was great to come home to after a long day in the lab, and they were great sounding boards for new ideas, listened to and shared rants about life’s highs and lows, and provided valuable reminders of life outside the lab. I thank my good friends Nate Kujawski and Kelly Allen-Kujawski for regular visits to the woods and exposure to small children in my nephew, Ethan, and niece, Nora. These visits never failed to provide much welcome perspective and rejuvenation. vii Finally, I thank my parents, Judith and Joseph, for giving me the genes and upbringing that make me experience and operate in the world the way I do, and for giving me the freedom to develop according to my own design. viii TABLE OF CONTENTS List of Figures and Tables ...................................................................................................... xiv List of Abbreviations .............................................................................................................. xvi Chapter 1 – Introduction: The Caenorhabditis elegans spermatheca as a model contractile tube ....................................................................................................... 1 1.1 – Abstract........................................................................................................................... 1 1.2 – Introduction ................................................................................................................... 1 1.3 – Contractile tubes are essential components of animal body plans ........................ 1 1.4 – C. elegans is a powerful model organism ................................................................... 2 1.5 – The C. elegans spermatheca is a powerful model contractile tube ......................... 3 1.6 – Calcium signaling regulates cellular contractility .................................................... 4 1.7 – Genetically encoded fluorescent calcium sensors and fluorescence microscopy enable in vivo study of calcium signaling in the spermatheca ....................... 4 1.8 – Conclusions and future directions .............................................................................. 5 Chapter 2 – Development of a lab bioimage informatics solution ................................... 7 2.1 – Abstract........................................................................................................................... 7 2.2 – Introduction ................................................................................................................... 7 2.3 – Motivation ...................................................................................................................... 9 2.4 – Design goals ................................................................................................................. 11 2.4.1 – Organization and research efficiency ............................................................... 13 2.4.1.1 – Unique identifier ........................................................................................
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