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Cellular Processes Regulating Cytoskeletal CELLULAR PROCESSES REGULATING CYTOSKELETAL SIGNALING, INSULIN RESISTANCE AND CALCIUM SIGNALING ARE COMMONLY MISREGULATED IN TYPE 1 AND TYPE 2 MYOTONIC DYSTROPHY PATIENTS by NRIPESH PRASAD A DISSERTATION Submitted in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in The Biotechnology Science and Engineering Program to The School of Graduate Studies of The University of Alabama in Huntsville HUNTSVILLE, ALABAMA 2014 ACKNOWLEDGEMENT The journey we take is supported by many others. Acknowledgement for a few might be just a trifle thing written on a piece of paper. Nevertheless, in the true essence, it gives us an opportunity to remember and express our feelings to those, whom we love, revere and share our secrets. Here I get a great chance to express my token of thanks to people who helped and supported me to complete this journey. It is my sublime duty to express my deepest sense of gratitude and veneration to my advisor Dr. Shawn E. Levy, Director, Genomics Service Lab, HudsonAlpha Institute for Biotechnology for his sincere and indelible inspiration, constant encouragement, constructive criticism, meticulous guidance, sustained interest, immense patience, and supportive nature throughout the investigation of the the research and preparation of this manuscript. I express my deepest sense of reverence and indebtedness to the esteemed members of my Advisory Committee, Dr(s). Joseph Ng, Debra Moriarity, Devin Absher, Gerg Cooper and Luis Cruz-Vera for their valuable suggestions and encouragement at various stages of my research and thesis writing. Sincere regards are due to, Dean, Graduate School, University of Alabama in Huntsville, Huntsville, AL, USA for providing all the necessary help and support. I also owe my gratitude to Dr. Rick Myers, Director, HudsonAlpha Institute for Biotechnology for all the help from time to time. I would also thank Dr. Andrew Link, Associate Professor of Pathology, Microbiology and Immunology, Vanderbilt University, TN; Dr. Bjarne Udd, Department of Neurology, Vasa Central Hospital, Finland and Dr. Ralf Krahe, Professor, Department of Genetics, vi University of Texas MD Anderson Cancer Center, Houston, TX, for helping me by providing necessary facilities to carry out the research work. I would also like to take this moment to remember late Dr. Gopi Podila; he was my academic advisor during my first year of graduate school and helped me begin graduate school successfully. I will always remember him for his supportive and caring nature towards me and my family. I express profound sense of love to my beloved wife Meenakshi and my endearing and adorable son Aayush who have always been a source of inspiration and encouragement for me. Their great sacrifice and constant support instilled a sense of responsibility and confidence into me that helped me get through the graduate school. A regard of love, affection of immeasurable inner rippling exclaims the entire viability of my respected mother Sangeeta Sharma, my father Kamesh Prasad, my brother Aditya, his lovely wife Jennifer and their cute little daughter Julia. Words are unlimited to express the unconditional support, love, care and cooperation extended by present and past members of Genomics Service Lab at HudsonAlpha Institute for Biotechnology, Huntsville, Alabama. I would like to thank Braden, Liz, Angela, Melanie, Joanna, John, Niki, Terri, Jack and Dan who were a constant source of encouragement for me during my research and thesis work. The help and guidance provided by senior scientists, post-docs and fellow graduate student is deeply acknowledged, without them it would have been difficult to pull through tough challenges. The pleasant company of Parimal Samir, Brittany Lasseigne, Joy Agee, Kenny Day, Kevin Bowling, Arnab Sen Gupta, Avinash vii Sreedasayam, Geethika Trivedi had been a source of positive inspiration and a fun experience. I am also grateful to all faculty and staff members of the Department of Biological Sciences, University of Alabama in Huntsville for all the help provided by them during my days as a graduate student. The University Teaching assistantship received during the first year and a half of my degree program is duly acknowledged. Also, I would like to express my deepest gratitude for the Graduate Research Assistantship I received from HudsonAlpha Institute for Biotechnology. Last but not the least; I would like to express my deepest and sincere thanks for the generosity of patients of type 1 and type 2 myotonic dystrophies from Finland who donated their muscle biopsies with the hope of helping others in the future. This list is obviously partial but allow me to submit that the omissions are inadvertent and I once again record my deep felt gratitude to all those who helped with me in this endeavor. Last but not the least, I thank the Almighty God for giving me courage and company of so many wonderful persons without whom I could not have succeeded in my pursuit. Huntsville (Nripesh Prasad) March, 2014 Author viii TABLE OF CONTENTS PAGE List of Figures ............................................................................................................... xiv List of Tables ...................................................................................................................xx Chapter 1 ...........................................................................................................................1 INTRODUCTION ............................................................................................................1 1. 1: Project objectives ...................................................................................................5 Chapter 2 ...........................................................................................................................7 REVIEW OF THE LITERATURE ................................................................................7 2.1: Muscular system .....................................................................................................7 2.2: Skeletal muscle system ...........................................................................................7 2.3: Muscle contraction ................................................................................................10 2.4: Simple tandem repetitive (STR) sequence and their molecular consequences ........................................................................................................11 2.5: Fundamental aspects of Myotonic Dystrophy .....................................................17 2.6: Prevalence of myotonic dystrophies .....................................................................20 2.7: Type 1 Myotonic Dystrophy (DM1) .....................................................................21 2.8: Type 2 Myotonic Dystrophy (DM2) .....................................................................23 2.9: Molecular pathomechanism of DM1 and DM2 disease: RNA- gain-of-function model .........................................................................................26 2.10: Role of MBNL protein in muscle development ..................................................29 2.11: Altered transcriptional and microRNA misregulation in DM patients. .................................................................................................................31 2.12: Microarray vs. Next generation sequencing technology ....................................32 Chapter 3 .........................................................................................................................35 MATERIALS AND METHODS ...................................................................................35 3.1: Procurement of human muscle biopsy samples ....................................................35 ix 3.2: Procurement of muscle biopsy samples from mouse models ...............................36 3.3: RNA extraction and its quality assessment...........................................................37 3.4: RNA-seq library preparation and sequencing .......................................................38 3.5: Small RNA (miRNA) library preparation and sequencing ...................................39 3.6: Processing of RNA-seq Reads ..............................................................................40 3.7: Processing of small RNA-seq Reads ....................................................................43 3.8: iTRAQ quantitation of the proteome ....................................................................44 3.9: Functional enrichment analysis of differentially expressed mRNAs and miRNAs ........................................................................................45 3.10: Validation studies for mRNA expression by Real-time quantitative PCR (RT-qPCR) ............................................................................46 Chapter 4 .........................................................................................................................47 RESULTS ........................................................................................................................47 4.1: Unbiased, novel integrated comparative analysis strategy adapted for studying transcriptional, miRNA and proteomics expression layout in skeletal muscle biopsies from DM1 and DM2 human patients. ..............................................................................................................47 4.2: Transcriptomics layout of the DM and control patients as identified by RNA-seq. ......................................................................................53
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