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Fontelonga Unr 0139D 12728.Pdf University of Nevada, Reno Development of Small Molecule Therapies Targeting Regeneration for the Treatment of Duchenne Muscular Dystrophy A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cellular and Molecular Pharmacology and Physiology by Tatiana M. Fontelonga Dr. Dean Burkin/Dissertation Advisor December, 2018 © by Tatiana M. Fontelonga 2018 All Rights Reserved THE GRADUATE SCHOOL We recommend that the dissertation prepared under our supervision by TATIANA M. FONTELONGA Entitled Development Of Small Molecule Therapies Targeting Regeneration For The Treatment Of Duchenne Muscular Dystrophy be accepted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Dean Burkin, Advisor Patricia Berninsone, Committee Member Normand LeBlanc, Committee Member Thomas Gould, Committee Member Thomas Kidd, Graduate School Representative David W. Zeh, Ph. D., Dean, Graduate School December, 2018 i Abstract Duchenne muscular dystrophy (DMD) is a devastating, X-linked, neuromuscular disease that affects 1 in 5,000 male children worldwide. DMD causes severe muscle wasting that confines individuals to wheelchairs and ventilators early on in life. Disease progression leads to pulmonary infections and cardiac failure, ultimately leading to the untimely death of patients. DMD is characterized by mutations in the Dmd gene, resulting in a loss of functional dystrophin protein. The lack of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein complex (DGC). In the absence of the DGC, the muscle is subject to contraction-induced sarcolemmal weakening, muscle tearing, fibrotic and inflammatory infiltration, calcium dysregulation and rounds of degeneration and regeneration affecting satellite cell populations. Currently, there is no cure for DMD and treatments are scarce. The α7β1 integrin has been implicated in increasing myogenic capacity of satellite cells therefore restoring muscle viability, increasing muscle force and preserving muscle function in dystrophic model mice. Our studies have identified two small molecule therapies capable of increasing α7β1 integrin and halting DMD disease progression. SU9516 was identified using a novel cell-based screen developed in our lab and Sunitinib was discovered as an FDA-approved, structural analog of SU9516. Both small molecules are hereafter characterized as α7β1 integrin enhancers capable of promoting myogenic regeneration. Specifically, Sunitinib stimulates satellite cell activation and increased myofiber fusion via transient inhibition of SHP-2/ERK1/2 ii and activation of the STAT3 pathway. Treatment with Sunitinib in mdx mice demonstrated decreased sarcolemmal damage via myofiber regeneration and enhanced structural support. Additionally, treatment with Sunitinib decreases fibrotic accumulation in the heart of dystrophic mice, making it an appealing therapeutic for DMD. This study identifies two small molecule compounds capable of halting skeletal muscle disease progression in the mdx mouse model of DMD, Sunitinib also showing potential as a treatment for dystrophic, dilated cardiomyopathy. iii Dedication To my mother Maria Jose, for her kind soul, endless love and constant support To my father Antonio, for always being there and helping me become the scientist I am today Thank you both for being my parents. iv Acknowledgements I would first like to thank Dr. Dean Burkin for accepting me into his lab and allowing me to work on such an amazing project, in a most rewarding field. Thank you for your mentorship and for allowing my independence in the lab, you helped me become the scientist I am today. I would also like to extend a large thank you to my committee members Dr. Patricia Berninsone for initially helping me get into the program, Dr. Normand LeBlanc for all his helpful questioning, Dr. Thomas Kidd for his mentorship throughout the years I’ve been at UNR and Dr. Thomas Gould for allowing me my first rotation in the CMPP program. Thank you all for taking time out of your hectic lives to help me become a better scientist. A big thank you to Dr. Mick Hitchcock for his support throughout my Ph.D. Thank you to Dr. Andreia Nunes, my Portuguese friend for all her help and for always fixing my computer problems! Thanks to Dr.’s Apurva Sarathy and Ryan Wuebbles for your scientific input. Thank you to Brennan Jordan, my faithful undergrad for spending hours helping me with my project. Thank you to Nicholas Bolden for his assistance on my project as well. A huge thank you to all my friends in the CMM building for making this experience a little less painful, I am lucky to have shared it with all of you. Suzanne Duan, thank you for making my days brighter with your sweet demeanor. Miguel Hernandez you will always make me laugh and I’ll be waiting for you on the East Coast. Jon Evasovic (aka Fallulah) thank you for always bringing me goodies and making my v days a little brighter. Dr. Mariam Ba thank you for your constant encouragement and friendship, I hope to soon see you running your own lab. Dante, thanks for always bailing me out of my car troubles! Vivian Cruz, thank you for your help in the lab but mostly for becoming one of my good friends. To my friends Samantha Lee, Kristina Sumauskaite, Cheryl Lee and Ariel Frey, thank you for the support and laughs. Thank you Marisela Dagda and the pharmacology admins, Annette, Lorraine and Alex for keeping things running. To Monica Rice, I wish I could’ve celebrated the day you graduated, you were truly a wonderful person, rest in peace my friend. Pamela Barraza-Flores, thank you for your disturbing sense of humor, for being there when science wasn’t working, for making me cry laughing, for taking the absolute worse candid photos of myself and for reviewing my dissertation. Thank you for all the trips we took together and for keeping me sane during this journey; but most of all, thank you for becoming one of my closest friends. I expect amazing things from you, GBC! A huge thank you to my mother, you are truly my biggest fan, you are the one person I don’t ever doubt loves me beyond all bounds, thank you for being my rock and for always picking up the phone when I need you but also for celebrating all my victories. Lady, you deserve a medal! To my father, thank you for making me question everything, for making me listen to classical music, for telling me tales about Albert Einstein, Wolfgang Pauli, Max Planck, etc., even when I didn’t want to listen (trust me, there were SO many tales). You made me the tough woman I am today, medal for you too! There is no obtaining a Ph.D. without the help, love and support of all these people and for that, I am truly thankful to you all. vi Table of Contents Abstract................................................................................................................................i Dedication..........................................................................................................................iii Acknowledgements...........................................................................................................iv Chapter 1 Introduction: Duchenne Muscular Dystrophy – The Path to Discovery of Small Molecule Treatments..........................................................................................1 Chapter 2 SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy.......................................50 Abstract..............................................................................................................................51 Introduction........................................................................................................................52 Materials and Methods.......................................................................................................54 Results................................................................................................................................62 Discussion..........................................................................................................................84 Chapter 3 Sunitinib promotes myogenic regeneration via transient SHP-2 inhibition/STAT3 activation and prevents Duchenne muscular dystrophy disease progression........................................................................................................................96 Abstract..............................................................................................................................97 Introduction........................................................................................................................98 Materials and Methods.....................................................................................................100 Results..............................................................................................................................105 Discussion........................................................................................................................123 Chapter 4 Cardiac Dystrophy and the Role of α7 Integrin..................................134 Abstract............................................................................................................................135 Introduction......................................................................................................................136 Materials and Methods.....................................................................................................147
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