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Characterization of a Mucopolysaccharidosis Type I and Galnac Transferase Deficiency Double Knockout Mouse Karan Gera Iowa State University

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Characterization of a Mucopolysaccharidosis Type I and Galnac Transferase Deficiency Double Knockout Mouse Karan Gera Iowa State University Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2018 Characterization of a Mucopolysaccharidosis Type I and GalNAc Transferase deficiency double knockout mouse Karan Gera Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Cell Biology Commons, Developmental Biology Commons, and the Molecular Biology Commons Recommended Citation Gera, Karan, "Characterization of a Mucopolysaccharidosis Type I and GalNAc Transferase deficiency double knockout mouse" (2018). Graduate Theses and Dissertations. 16582. https://lib.dr.iastate.edu/etd/16582 This Thesis is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Characterization of a Mucopolysaccharidosis Type I and GalNAc Transferase deficiency double knockout mouse by Karan Gera A thesis submitted to the graduate faculty in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Major: Molecular, Cellular and Developmental Biology Program of Study Committee: N. Matthew Ellinwood, Major Professor Jodi Dee Smith Donald Sakaguchi The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this thesis. The Graduate College will ensure this thesis is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2018 Copyright © Karan Gera, 2018. All rights reserved. ii TABLE OF CONTENTS LIST OF FIGURES .......................................................................................................... iv LIST OF TABLES ............................................................................................................. v LIST OF ABBREVIATIONS ........................................................................................... vi ACKNOWLEDGMENTS ............................................................................................... vii ABSTRACT .................................................................................................................... viii Endosomal-Lysosomal Vesicle Trafficking Pathway ................................................ 10 Lysosomal Storage Diseases ...................................................................................... 12 The Mucopolysaccharidoses ....................................................................................... 13 History and clinical characteristics........................................................................ 16 Treatment of MPS diseases ................................................................................... 19 Mucopolysaccharidosis Type I ................................................................................... 20 Molecular Genetics................................................................................................ 21 Clinical Pathology of MPS I ....................................................................................... 21 Biochemical and histological features ................................................................... 21 Morphological observations .................................................................................. 27 Central nervous system morphology ................................................................ 27 Bone and joint disease ...................................................................................... 27 Cardiovascular and respiratory pathology ....................................................... 28 Ophthalmic Pathology ...................................................................................... 28 Cognitive and Behavioral Problems ................................................................ 29 Animal Models of MPS I ................................................................................. 29 Therapeutic Strategies for MPS I ............................................................................... 31 Improvement Of α-L-Iduronidase Activity ........................................................... 32 Hematopoietic stem cell transplantation (HSCT) ............................................ 32 Enzyme replacement therapy (ERT) ................................................................ 34 Gene Therapy ................................................................................................... 37 Substrate Deprivation Therapy ........................................................................ 40 Management of Secondary Immune Responses .............................................. 41 References .................................................................................................................. 42 CHAPTER 2: CHARACTERIZATION OF A MUCOPOLYSACCHARIDOSIS TYPE I AND GALNAC TRANSFERASE DEFICIENCY DOUBLE KNOCKOUT MOUSE............................................................................................................................ 49 Introduction ................................................................................................................ 49 Materials & Methods .................................................................................................. 53 Experimental animals ............................................................................................ 53 Genotyping ............................................................................................................ 54 Clinical observations ............................................................................................. 55 Euthanasia and tissue processing .......................................................................... 55 iii Results ........................................................................................................................ 56 Genotyping ............................................................................................................ 56 Clinical observations ............................................................................................. 56 Gross findings........................................................................................................ 57 References .................................................................................................................. 59 CHAPTER 3: CONCLUSIONS ...................................................................................... 61 REFERENCES ................................................................................................................ 62 iv LIST OF FIGURES Figure 1.1 The endosomal-lysosomal pathway ..............................................................11 Figure 1.2 Classification of Lysosomal Storage Diseases ..............................................14 Figure 1.3 Degradation pathways and associated enzymes for various GAGs ..............15 Figure 1.4 Heparan sulfate degradation pathway ...........................................................23 Figure 1.5 Dermatan sulfate degradation pathway .........................................................24 Figure 2.1. Idua amplified PCR sequences on a 2% agarose gel……………................56 Figure 2.2 GalNAcT amplified PCR sequences on a 2% agarose gel…....……............56 Figure 2.3 Gross findings of 20 - week old mice upon dissection………...……...........58 v LIST OF TABLES Table 1.1. A list of the Mucopolysaccharidoses ............................................................18 Table 2.1 Specifications of the primers used in PCR genotyping ..................................54 vi LIST OF ABBREVIATIONS AAV Adeno-associated virus Idua α-L-Iduronidase (murine) ATP Adenosine Triphosphate LSD Lysosomal Storage Disease CNS Central nervous system KS Keratan sulfate CS Chondroitin sulfate mAb Monoclonal Antibody CSF Cerebrospinal Fluid MPS Mucopolysaccharidosis Damage associated molecular Online Mendelian Inheritance DAMP OMIM pattern in Man DNA Deoxyribonucleic acid PCR Polymerase Chain Reaction Recombinant deoxyribonucleic DS Dermatan sulfate rDNA acid ECM Extracellular matrix ROS Reactive oxygen species EDTA Ethylenediaminetetraacetic acid TGN Trans-golgi network ERT Enzyme replacement therapy ZFN Zinc-finger nuclease ES/ESC Embryonic Stem Cells GAG Glycosaminoglycan β-1,4-N- GalNAcT acetylgalactosaminyltransferase GTP Guanosine Triphosphate HA Hyaluronic acid HLA Human leukocyte antigen HS Heparan sulfate Hematopoietic stem cell HSCT transplantation HSPG Heparan sulfate proteoglycan IDUA α-L-Iduronidase (human) vii ACKNOWLEDGMENTS The research illustrated in this thesis reflects one of the most crucial phases of my growth and development in the field of biological sciences, which would not have been possible without the staunch, unerring tutelage and guidance of my major professor Dr. N. Matthew Ellinwood. For introducing me to the lysosomal storage diseases and inspiring me to be the best version of myself while striving to work in the field to serve a greater purpose, I will be forever grateful to him. I extend my gratitude to Dr. Jodi Smith and Dr. Don Sakaguchi, both of whom have been not just my committee members but also my instructors throughout this time, keenly advising me where necessary. This was not an individual endeavor. It is the culmination
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