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Microrna Regulation During Neuroinflammation: from Junk DNA to a Phd Thesis

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Microrna Regulation During Neuroinflammation: from Junk DNA to a Phd Thesis microRNA regulation during neuroinflammation: from junk DNA to a PhD thesis Camille A. Juźwik A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy in Neurological Sciences Integrated Program in Neuroscience Department of Neurology and Neurosurgery - McGill University 3801 University Street - Montreal, QC, H3A 2B4, Canada March 2019 © Camille A. Juźwik, 2019 All rights reserved Table of Contents 1 Forward………..……………………………………………………………. 5 1.1 Abstract………………………………………………………………………....................... 5 1.2 Résumé………………………………………………………………………....................... 6 1.3 Acknowledgments…………………………………………………………......................... 8 1.4 Preface and Author Contributions.…...……………………………………………........... 10 1.5 List of Figures and Tables…………………………………………………........................ 12 1.6 List of Abbreviations…….…………………………………………………........................ 15 1.7 List of Publications...…………………………………………………………...................... 17 2 Chapter 1. Introduction…………………………………………………... 19 2.1 General Introduction………………………………………………………………………. 19 2.2 Multiple Sclerosis……..…………………………………………………………………… 22 2.2.1 White matter lesions: axonal pathology….…………………………….............................................................. 24 2.2.2 Gray matter lesions: soma pathology ……….................................................................................................. 25 2.2.3 Experimental autoimmune encephalomyelitis…………………………………….............................................. 27 2.2.4 Not all inflammation is bad…………………... …………………………............................................................. 27 2.3 Regulators of axon regeneration………………………………………….…………….. 29 2.3.1 Inflammatory mediators of neuronal repair and regeneration……………....................................................... 30 2.3.2 Intrinsic neuronal mediators regeneration………….............................................………………..................... 31 2.4 microRNA…………………………………………………………………….……………… 32 2.4.1 microRNA biogenesis and function……..….…………….............................................…………..................... 33 2.4.2 microRNA in central nervous system disease and injury……………….......................................................... 36 2.4.3 Note on microRNA nomenclature…………………………………………………………………………………… 37 2.5 Rationale…………………………………………………………………………………….. 38 Results………….......................................…......................................... 39 Preface……………………………………………………………………………………….. 40 3 Chapter 2. Neuronal microRNA regulation in Experimental Autoimmune Encephalomyelitis………….......................................... 41 3.1 Abstract……………………………………………………………………..……………….. 42 3.2 Introduction…………………………………………………………………………………. 43 3.3 Results……………………………………………………………………………………….. 45 3.3.1 Differential miRNA expression over the course of EAE in lumbar motor neurons......................……............ 48 3.3.2 Differential miRNA expression over the course of EAE in the RGC layer………………………..……............ 52 3.3.3 miR-Seq identified and validated miRNAs in EAE neurons are found regulated in other EAE/MS tissue…. 54 3.3.4 In silico assessment of putative targets identifies novel pathways predicted to be affected in the neurons of EAE mice. ………………………..……............………………………..……............………………………….. 54 3.4 Discussion…………………………………………………………………………………... 61 3.5 Acknowledgments…………………………………………………………………………. 66 3.6 Competing Financial Interests…………………………………………………………... 66 3.7 Materials and Methods……………………………………………………………………. 67 3.7.1 Active EAE Disease Induction and Scoring.......................……............……………..……............…………… 67 3.7.2 CNS tissue isolation.………………………..……...............……............……………..……............……………. 67 3.7.3 Laser capture microdissection.…....……............……………..……............…………………………………….. 67 3.7.4 RNA extraction from LCM tissue...………………………..……............…………...........………………………. 68 3.7.5 Cell cultures......................……...............……............……………..……............………………………………. 68 3.7.6 Next-Generation Sequencing (NGS)………………………..…….......................………………………………. 69 3.7.7 Quantitative RT-PCR (qRT-PCR)….……………..…….......................………………………………………….. 70 3.7.8 In silico assessment of predicted targets..….……………..…….......................………………………………… 71 3.8 Supplementary Tables.…………………………………………………………………… 72 Preface……………………………………………………………………………………….. 81 4 Chapter 3. MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis……………………… 82 4.1 Abstract……………………………………………………………………..……………….. 83 4.2 Introduction…………………………………………………………………………………. 84 4.3 Results……………………………………………………………………………………….. 86 4.3.1 miR-23a-3p, miR-27a-3p, miR-146a-5p and miR-223-3p are upregulated in EAE and MS…………………… 86 4.3.2 miR-27a-3p and miR-223-3p are neuroprotective ………………………..……..................……...................... 88 4.3.3 miR-223 overexpression rescues axonal degeneration in EAE optic nerve …................……....................... 90 2 4.3.4 miR-27a-3p and miR-223-3p mediate neuroprotection through glutamate receptor (GluR) signaling............. 95 4.4 Discussion…………………………………………………………………………………... 101 4.5 Acknowledgments and Funding………………………………………...………………. 105 4.6 Competing Financial Interests…………………………………………………………... 105 4.7 Materials and Methods……………………………………………………………………. 106 4.7.1 Experimental animals……………………………………………………………………...………………………… 106 4.7.2 Preparation of peripheral blood mononuclear cell conditioned media (PBMC-CM).......................……........ 106 4.7.3 Degeneration assays.………………………..……...............……............…………............…………………..... 106 4.7.4 Neuronal survival assay...…………………..……...............……............…………............…………………..... 107 4.7.5 Cell viability.…....……............……………..……............……………………………………..…............……….. 107 4.7.6 Quantitative RT-PCR (qRT-PCR)..………………………..……............…………...........………………………. 107 4.7.7 Active EAE Induction......................……...............……............……………..……............…………………….. 107 4.7.8 Laser-capture microdissection………………………..…….......................…………………………………….... 108 4.7.9 Human brain samples ….……………..…….......................…………………………………………………….... 108 4.7.10 Histology…………….. ….……………..…….......................…………………………………………………….... 109 4.7.11 Whole mount optic nerve staining and clearing ........................……............……………..………………........ 109 4.7.12 Immunohistochemistry (IHC) in retinal sections………………………………………………………………..…. 109 4.7.13 Intravitreal injection and AAV2-virus delivery.………………………..……...............……............…………..... 110 4.7.14 Quantification of RGC survival……………………..............……............……………..………………................ 110 4.7.15 In silico assessment of predicated targets.…....……............……………..……............………………………. 110 4.7.16 Luciferase assays.…....……............……………..……............…………………………….……………………. 111 4.7.17 Statistical analyses..………………………..……............…………...........……………………….……………… 111 4.8 Supplementary Figures and Tables.……………………………………………………. 112 Preface……………………………………………………………………………………….. 118 5 Chapter 4. Inhibition of miR-383 promotes axon regeneration following injury by a distributed relief of targets……………………... 119 5.1 Abstract……………………………………………………………………..……………….. 120 5.2 Introduction…………………………………………………………………………………. 121 5.3 Results……………………………………………………………………………………….. 124 5.3.1 miR-383-5p is downregulated in growth-permissive conditions and upregulated in growth-inhibitory conditions.………………………..…….............……..…….............……..…….............……..…….................... 124 5.3.2 miR-383-5p downregulation is sufficient to promote axon growth .………………………..……..................... 127 5.3.3 Inhibition of miR-383-5p promotes RGC axon regeneration following ONC ........................……................. 129 5.3.4 miR-383-5p is regulated by CNTF…….…................……........................……......................……................. 131 5.3.5 miR-383-5p targets multiple genes contributing to axon regeneration....……......................……................. 132 5.3.6 Crmp2 and Prdx3 regulates neurite outgrowth in vitro…........................……......................……................. 133 5.3.7 Crmp2 and Prdx3 are upregulated in retinal neurons following zymosan-primed ONC.......……................. 135 5.4 Discussion…………………………………………………………………………………... 136 5.5 Acknowledgments…………………………………………………………………………. 140 5.6 Competing Financial Interests…………………………………………………………... 140 5.7 Materials and Methods……………………………………………………………………. 141 5.7.1 Preparation of conditioned media.…….........……............…………............………………….......................... 141 5.7.2 Neuronal cultures.………………………..……...............……............…………............………………….......... 141 5.7.3 Semi-quantitative RT-PCR.…....……............……………..……............…………………………………........... 142 5.7.4 Quantitative RT-PCR (qRT-PCR)..………………………..……............…………...........………………………. 144 5.7.5 Luciferase assays......................……...............……............……………..……............………………………... 144 5.7.6 miR-383-5p sponge generation………………………..…….......................…………………………………….. 145 5.7.7 In vivo axonal injury ….……………..…….......................……………………………………………………....... 145 5.7.8 Whole mount optic nerve clearing and axonal quantification.......................……............…………………….. 146 5.7.9 In silico assessment of predicated targets.…....……............……………..……............……………………….
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