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IN VIVO MODELS to INVESTIGATE MECHANISMS of RARE BONE PATHOLOGIES and THERAPEUTIC TREATMENT a Dissertation by DIARRA KEVIN WILLI

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IN VIVO MODELS to INVESTIGATE MECHANISMS of RARE BONE PATHOLOGIES and THERAPEUTIC TREATMENT a Dissertation by DIARRA KEVIN WILLI IN VIVO MODELS TO INVESTIGATE MECHANISMS OF RARE BONE PATHOLOGIES AND THERAPEUTIC TREATMENT A Dissertation by DIARRA KEVIN WILLIAMS Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Larry J. Suva Co-Chair of Committee, Dana Gaddy Committee Members, Robert Burghardt Ken Muneoka Head of Department, Larry J. Suva August 2018 Major Subject: Biomedical Sciences Copyright 2018 Diarra K. Williams ABSTRACT Genetic disorders associated with skeletal disease are extremely complex and vary greatly in their clinical phenotypes. Thus, in vivo models that accurately recapitulate these rare bone pathologies are essential for understanding the mechanisms of disease and can serve as tools for evaluating therapeutic treatments while providing insight into normal bone physiology. However, by their nature these rare diseases combined with a deficiency in animal models can significantly delay mechanistic understanding and even therapeutic development. Therefore, the goal of this work was to evaluate murine models of Down syndrome (DS) and develop an appropriate model of human Hypophosphatasia (HPP). The low bone mass phenotype in DS is defined by low bone turnover due to decreased osteoclast and osteoblast activity, decreasing the utility of anti-resorptive agents in people with DS. Thus, we examined the effects of a known bone anabolic agent – sclerostin antibody (SclAb). Male Ts65Dn and age-matched WT littermate mice (8 weeks old) were treated with 4 weekly i.v. injections of 100 mg/kg SclAb. Analysis by DXA, microCT, and ex vivo bone marrow cultures revealed that SclAb had a significant anabolic effect on both controls and Ts65Dn DS mice that was osteoblast mediated, without significant changes in osteoclast numbers. Additionally, comparative gene profiling by RNAseq of whole femurs from 7 month old male Ts65Dn mice and WT provided insight into the molecular mechanisms underlying this unusual and rare bone phenotype. Moreover, we successfully generated the first large animal model of a rare human bone disease using CRISPR/Cas9 to introduce a single point mutation in the tissue nonspecific alkaline phosphatase (TNSALP) gene (ALPL) (1077C>G) in sheep, thereby creating HPP. Compared to wild-type (WT) controls, HPP sheep have reduced serum alkaline phosphatase ii activity, decreased tail vertebral bone size, and metaphyseal flaring, consistent with mineralization deficits observed in human HPP. Oral radiographs and computed tomography revealed thin dentin and wide pulp chambers in incisors, and radiolucency of jaws in HPP vs. WT sheep. Skeletal muscle biopsies reveal aberrant fiber size and mitochondrial cristae structure in HPP vs. WT sheep. These genetically engineered sheep phenocopy HPP and provide a novel large animal platform for the longitudinal study of HPP progression, as well as other rare bone diseases. iii DEDICATION To the people living with rare disease and their families; To the boys and girls whom were ever made to feel as if you were not good enough or told you were anything, but amazing; And lastly but certainly not least, to my big brother Chester Adisa Guster and all the young black men and women taken from this earth too soon; the individuals we lost to the struggle; To our brothers and sisters who will never have the opportunity to achieve milestones such as this one. I dedicate this dissertation to you! Let this body of work serve as proof that all things are possible with determination and belief. Keep pushing forward, keep fighting, and never listen to the “nay-sayers”! With Love, D! iv ACKNOWLEDGEMENTS First and foremost, I have to acknowledge and thank my family who have supported through not only this degree, but every endeavor I have pursued. I am especially thankful for my mom (Eunice Guster-Bray) and my sister (Baraka Williams) for their tireless support and everlasting love during the good times and the trying ones. To my aunt (Bigsis), thank you for patience, your love, and your support through all these years. Life as a graduate student can be very demanding and it sometimes take a team of individuals and mentors to help one through this process. With that, I am thankful my advisors and mentors Dr. Larry Suva and Dr. Dana Gaddy. They have been instrumental to my matriculation through this degree program. I thank you both for your guidance, patience, and all of your efforts towards my academic, professional, and personal development these past 5 years. Their teachings have extended well beyond the laboratory and they were shy about provided helping me whenever I needed it. I thank my committee members, Dr. Robert Burghart and Dr. Ken Muneoka, for their guidance and advisement throughout this journey. To all the faculty and staff from UAMS and TAMU that have encouraged me along the way, I thank you. Lastly, to all my friends that have I met along the way, I cannot say thank you enough for the great times and amazing memories. v CONTRIBUTORS AND FUNDING SOURCES This work was supervised by a dissertation committee consisting of Professors Larry J. Suva and Ken Muneoka from the Department of Veterinary Physiology and Pharmacology, Professor Dana Gaddy from the Department of Veterinary Integrative Biosciences, and Professor Robert Burghardt, Dean of the Office of Graduate Studies and Research – from the College of Veterinary Medicine and Biomedical Science. Tissue sectioning and staining for paraffin and plastic slides in Chapter III and V was performed by Alyssa Falck (AF) and in Chapter IV by Frances L. Swain. Ex vivo bone marrow cultures were achieved by Diarra K. Williams (DKW) and Nisreen S. Akel (NSA) in Chapter IV and by DKW, AF, and Shannon Huggins (SH) in Chapter III. Enumeration of ex vivo cultures was done by Jamie Schmidt in Chapter IV under the supervision of DKW and by DKW alone in Chapter III. Chapter V experimental design was achieved by DKW, SH, Larry J. Suva (LJS), and Dana Gaddy (DG) in collaboration with the Reproductive Science Laboratory (RSL) under the supervision of Charles R. Long (CRL). MicroCT for Chapters II-V were performed by AF or LJS. RNA sequencing in Chapter IV was performed by the Genomics Core at the University of Arkansas for Medical Science (UAMS) under the supervision of Stewart MacLeod and Kartik Shankar, and RNA extraction, GO analysis, Signal Pathway mapping and analysis, and other analysis of RNA seq data was performed by DKW. Muscle samples in Chapter V were prepared by Ross Payne at the CVM Imaging Center and imaged by DG and AF. The primary sheep fibroblasts were a gift from RSL. All other work conducted for the dissertation was completed by the student. The research for Chapter V was partially supported by the Center for Cell and Organ Biotechnology (CCOB) Innovation Kitchen Grant (awarded to DKW) and Texas A&M vi University (LJS/DG). Graduate study was supported by the Initiative to Maximize Student Diversity Training Grant from University of Arkansas for Medical Science and the Porter Physiology Development Fellowship from the American Physiological Society. vii NOMENCLATURE ALPL Alkaline Phosphatase ACTRIIA Activin Receptor Type-IIA BMD Bone Mineral Density BMU Basic Multicellular Unit BV/TV Bone Volume / Total Volume Cas CRISPR-associated Genes CRISPR Clustered Regularly Interspaced Short Palindromic Repeats DNA Deoxyribonucleic Acid DXA Dual Energy X-ray Absorptionetry DMP1 Dentin Matrix Protein 1 DS Down syndrome FSH Follice Stimulating Hormone GFP Green Fluorescent Protein HDR Homology Directed Repair HPP Hypophosphatasia Inh Inhibin mCSF Macrophage Colony Stimulating Factor MSC Mesenchymal Stem Cell mTOR Mammalian Target of Rapamycin OPG Osteoprotegerin OPN Osteopontin viii PAM Protospacer Adjacent Motif PEA Phosphoethanolamine PCR Polymerase Chain Reaction PLP Pyridoxal 5’ Phosphate PPi Inorganic Pyrophosphate PTH Parathyroid Hormone RANK Receptor Activator of Nuclear Factor kappa B RANKL Receptor Activator of Nuclear Factor kappa B Ligand RNA Ribonucleic Acid RUNX1 Runt-related Transcription Factor 1 RUNX2 Runt-related Transcription Factor 2 RTSK Serine/Threonine Receptor Kinase SOST Sclerostin sFRP` Secreted Frizzled-Related Protein TGFβ Transforming Growth Factor Beta TNF Tumor Necrosis Factor TNSALP Tissue Nonspecific Alkaline Phosphatase TbTh Trabecular Thickness TbN Trabecular Number TbSp Trabecular Spacing TRAF6 Tumor Necrosis Factor Receptor Associated Factor 6 WT Wild Type ix TABLE OF CONTENTS Page ABSTRACT .............................................................................................................................. ii DEDICATION .......................................................................................................................... iv ACKNOWLEDGEMENTS.........................................................................................................v CONTRIBUTORS AND FUNDING SOURCES ...................................................................... vi NOMENCLATURE ................................................................................................................ viii TABLE OF CONTENTS ............................................................................................................x LIST OF FIGURES ................................................................................................................ xiii LIST OF TABLES .................................................................................................................... xv CHAPTER
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