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Signature Redacted Redacted Engineering Genetically-Encodable MRI Contrast Agents for in vivo Imaging By Yuri Matsumoto B.S. Chemistry Massachusetts Institute of Technology, 2006 SUBMITTED TO THE DEPARTMENT OF BIOLOGICAL ENGINEERING IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN BIOLOGICAL ENGINEERING AT THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY FEBRUARY 2014 MASSACHUSETTS 1ThJN 0 Yuri Matsumoto, 2014. All rights reserved. OF TECHNOLOGY The author hereby grants MIT permission to reproduce JUN 3 0 201 and to distribute publicly paper and electronic copies of this thesis document in whole or in part LIBRARIES i any medium now known or hereafter created. Signature of Author: Signature redacted Department of Biological Engineering January 1, 2014 Certified by:_Signature redacted Alan P. Jasanoff Associate Professor of Biological Engineering Nuclear Science and Engineering, and Brain and Cognitive Sciences Thesis Supervisor redacted CertifiedSignature Forest White Associate Professor of Biological Engineering Chairman, Graduate Program Committee 1 2 Thesis Committee A ccepted by..................................................................................K . D ane W ittrup Professor of Chemical & Biological Engineering Chairman of Thesis Committee A ccepted by....................................................................................A lan P. Jasanoff Associate Professor of Biological Engineering, Nuclear Science and Engineering, and Brain and Cognitive Sciences Thesis Supervisor A ccepted by.................................................................................... Angela B elcher W.M. Keck Professor of Energy in Materials Science and Engineering and Biological Engineering Thesis Committee Member 3 Abstract Magnetic resonance imaging (MRI) is gaining recognition as a powerful tool in biological research, offering non-invasive access to anatomy and activity at high spatial and temporal resolution. However, the range of biological phenomena accessible to measurement by MRI is limited, due to a current lack of molecular-level methods for detecting physiological processes in living organisms. One way to overcome this limitation is to develop contrast agents that report physiological events at a molecular level. Traditionally MRI contrast agents have been based on small molecules that chelate paramagnetic ions such as Gd (III), but synthesis and delivery of such exogenously applied agents are complicated. Genetically-encodable MRI sensors may overcome some of these issues. In this thesis, we describe new class of MRI contrast agents which will be broadly applicable as genetically-controlled tools for in vivo imaging. The major goal of my thesis research was to improve the sensitivity of the existing protein-based MRI contrast agent, ferritin (Ft) by inducing it to accumulate larger number of iron atoms per particle in a physiological environment. Using a high throughput genetic screening process, we obtained Ft mutants that show threefold greater cellular iron accumulation than mammalian heavy chain Ft. In another project, we used the engineered Ft to develop a dynamic gene reporter that responds to changes in gene expression levels in vivo via aggregation-dependent MRI contrast changes. Successful creation of genetically-encodable MRI contrast agents that are robust and sensitive enough to be applied in vivo will enable neuroscientists and biologists to study molecular processes of living subjects. Thesis Supervisor: Alan P. Jasanoff Title: Associate Professor of Biological Engineering, Brain and Cognitive Sciences and Nuclear Science and Engineering 4 Acknowledgements I would like to thank my advisor, Alan Jasanoff for his continuous support while I pursued my doctoral degree. He has generously supported me financially and intellectually whenever I needed help with my projects. He respected my decisions and allowed me to explore many different ideas which helped me gain valuable experience as a scientist. I would also like to thank my committee members, Dane Wittrup and Angela Belcher for their helpful insights and advice with my thesis work. I am also grateful to my former and current colleagues in Jasanoff lab. In particular, I would like to thank Tatjana Atanasijevic and Gil Westmeyer for teaching me laboratory techniques when I first started working in the lab. I would like to thank Mariya Barch and Victor Lelyveld for helpful discussions with my projects. I would like to thank various facilities at MIT (CSBI biosil cluster, MIT Center for Materials Science and Engineering, nanotechnology materials core facility, and flow cytometry core facility) which helped me execute experiments for my publications. I am grateful to my funding sources, a Friends of the McGovern Institute Fellowship and a Siebel Scholar Fellowship for providing financial support in my 3 rd and 5th year of my Ph.D. I am also extremely grateful to my parents in Japan who have raised me with patience while I explored the world with overwhelming curiosity. My mother in particular has been my best friend and mentor for as long as I can remember. Finally, I would like to express the deepest appreciation to my husband, Nicholas Tham for being kind, patient and resourceful while I struggled through my thesis work. Besides being a responsible husband, he has been my technical support, chef, therapist and workout buddy. I would not have been able to complete my study without his support and for that I am eternally indebted to him. 5 Table of Contents A b stract..................................................................................................... 4 A cknow ledgem ents......................................................................................... 5 T able of C ontents............................................................................................6 1. Introduction 1.1. Goals of molecular imaging ..................................................................... 9 1.2. Magnetic resonance imaging (MRI) as a molecular imaging tool .......................... 9 1.3. Theoretical basis of MRI contrast agents: TI and T2 contrast agents..................... 11 1.4. Advantages of protein-based MRI contrast agent.............................................13 1.5. R elaxivity of Ft.................................................................................... 14 1.6. Ft-based MRI gene reporter: Initial studies.................................................... 15 1.7. Advantages and challenges of Ft-based MRI contrast agent............................... 16 2. Engineering intracellular biomineralization to produce hypermagnetic genetically- encoded nanoparticles 2.1. A bstract ......................................................................................... .. 18 2.2. Introduction, results and discussions ............................................................ 19 2.3. M aterials and m ethods ............................................................................ 25 2.4. Acknowledgements .............................................................................. 31 2.5. Figure captions ................................................................................... 32 2 .6. F igures .......................................................................................... ... 35 2.7. Supplem entary m aterial ........................................................................... 39 3. Clusters of genetically engineered hypermagnetic nanoparticles report dynamic changes with MRI 3.1. Abstract ......................................................................................... 45 6 3.2. Introduction, results and discussions .......................................................... 46 3.3. Materials and methods ......................................................................... 50 3.4. Acknowledgements .............................................................................. 55 3.5. F igure caption s ...................................................................................... 55 3 .6 . F ig u res ............................................................................................... 5 8 3.7. Supplementary Material ......................................................................... 61 4. T2 relaxation induced by clusters of superparamagnetic nanoparticles: Monte Carlo simulations. 4 .1. Ab stract ........................................................................................... 64 4.2. Introduction ....................................................................................... 65 4 .3. M ethods ............................................................................................ 67 4.4. Results and discussion ......................................................................... 69 4.5. C onclusions ....................................................................................... 74 4.6. A cknow ledgem ents ................................................................................ 75 5. Conclusions and future directions 5.1. SPFt-L55P nanoparticles and the genetic screen............................................. 76 5.2. Ft-based dynamic gene reporter ............................................................... 75 Appendix A: Metalloprotein-based MRI probes (review article) ..................................... 79 Appendix B: Towards finding mutant ferritins with higher magnetic moment by a high gradient m agnetic cell sorting screen...............................................................................106
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