DOCSLIB.ORG

Exploring the Molecular Pathophysiological Mechanisms In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Exploring the Molecular Pathophysiological Mechanisms In Exploring the Molecular Pathophysiological Mechanisms in Hypomyelinating Leukodystrophies Resulting from Recessive Mutations in EPRS, RARS, and DARS Mariana Gutierrez Salazar, Human Genetics, McGill University, Montreal May 2017 A thesis submitted to McGill University in partial fulfillment of the degree of Master of Science © Mariana Gutierrez Salazar, 2017 1 Table of Contents Abstract ..................................................................................................................................... 6 Résumé...................................................................................................................................... 8 Acknowledgements ................................................................................................................. 10 List of Figures and Tables ...................................................................................................... 12 List of Abbreviations .............................................................................................................. 14 Chapter 1: Introduction 1.1 Overview ...................................................................................................................... 21 1.1.2 Hypothesis .......................................................................................................... 23 1.1.3 Project Rationale ................................................................................................ 23 1.1.4 Specific Aims ..................................................................................................... 24 1.2 Introduction to Leukodystrophies ................................................................................ 25 1.2.1 What are leukodystrophies? ............................................................................... 25 1.2.2 Characterization of leukodystrophies................................................................. 26 1.2.3 Non-hypomyelinating Leukodystrophies ........................................................... 27 1.2.4 Hypomyelinating Leukodystrophies .................................................................. 27 1.3 POLR3-Related Leukodystrophy ................................................................................. 28 1.3.1 Clinical aspects of POLR3-related Leukodystrophy ......................................... 28 1.3.2 Genetic Etiology of POLR3-related Leukodystrophy ....................................... 29 1.3.3 RNA Polymerase III (POLR3) .......................................................................... 29 1.4 Canonical Function of Aminoacyl-tRNA Synthetases ................................................ 31 1.4.1 Mechanism of Aminoacylation .......................................................................... 31 1.4.2 Structural components of ARS .......................................................................... 32 2 1.4.3 Subcellular localization ...................................................................................... 33 1.4.4 Aminoacyl-tRNA synthetases form a multisynthetase complex ....................... 33 1.4.5 Multisynthetase Complex Structure ................................................................... 34 1.5 Non-canonical functions of ARS ................................................................................. 36 1.5.1 ARS Functions in Diverse Cellular Processes ................................................... 36 1.5.2 EPRS is a member of the INF--activated inhibitor of translation (GAIT) complex ............................................................................................................. 39 1.5.3 DARS can affect cell migration ......................................................................... 40 1.5.4 RARS modulates the secretion of AIMP1 ......................................................... 41 1.6 ARSs in Central and Peripheral Nervous System Diseases ......................................... 42 1.7 Mutations in ARS genes cause Hypomyelinating Leukodystrophy ............................ 44 1.7.1 Mutations in DARS cause Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL) .......................................................... 44 1.7.2 Mutations in RARS cause HLD .......................................................................... 44 Chapter 2: Materials and Methods 2.1 Identification of EPRS mutations in HLD patients ...................................................... 47 2.1.1 Patients and DNA Extraction from Blood ......................................................... 47 2.1.2 Whole Exome Sequencing (WES) and Analysis ............................................... 47 2.1.3 Mutation Validation by PCR and Sanger Sequencing ....................................... 47 2.2 Cell Culture .................................................................................................................. 48 2.2.1 HeLa, HEK 293, and fibroblast culture ............................................................. 48 2.3 Western Blot ................................................................................................................ 49 2.3.1 Protein Extraction and Quantification................................................................ 49 3 2.3.2 Western Blot ...................................................................................................... 49 2.4 Cycloheximide Chase Assay ........................................................................................ 51 2.4.1 FLAG-tagged vector Construction .................................................................... 51 2.4.2 Cell Transfection of 3xFLAG-tagged EPRS, RARS, and DARS...................... 52 2.4.3 Cycloheximide Chase Assay .............................................................................. 52 2.5 Affinity Purification coupled to Mass Spectrometry ................................................... 53 2.5.1 FLAG-tagged Affinity Purification coupled to Mass Spectrometry .................. 53 2.5.2 Generation of BioID vectors and BioID cell lines ............................................. 54 2.5.3 Proximity-dependent biotinylation followed by AP-MS (BioID-MS) ............. 55 2.5.4 Preparation of samples for Mass Spectrometry ................................................. 55 2.5.5 Mass Spectrometry ............................................................................................. 56 2.5.6 Mass Spectrometry Data Analysis ..................................................................... 57 2.6 In vitro purification of hPRS, RARS and DARS ......................................................... 58 2.6.1 GST-tagged vectors construction ....................................................................... 58 2.6.2 In vitro expression of GST tagged protein ......................................................... 58 2.6.3 Affinity Purification of GST fusion protein ....................................................... 59 Chapter 3: Results 3.1 Recessive Mutations in EPRS cause Hypomyelinating Leukodystrophy .................... 62 3.1.1 Clinical Presentation .......................................................................................... 62 3.1.2 Identification of EPRS mutations by WES ........................................................ 64 3.2 HLD patient fibroblasts’ show decreased EPRS protein expression ........................... 66 3.3 EPRSP1115R mutant gene product has decreased protein stability ................................ 67 4 3.4 HLD-causing mutations in RARS and DARS cause alterations in relative protein stability of gene products ............................................................................................ 68 3.5 HLD causing mutations in EPRS, RARS, and DARS gene products do not affect the assembly of the MSC as monitored by AP-MS .......................................................... 68 3.6 HLD-causing mutations in RARS and DARS gene products do not affect assembly of the MSC as monitored by BioID-MS ......................................................................... 70 3.7 BioID-MS to assess protein-protein interactions with RARS and DARS ................... 71 3.7.1 BioID-MS and AP-MS results indicate that the MSC does not transiently interact with other ARS proteins ................................................................................ 71 3.7.2 GFAP interacts with RARS and DARS in both WT and MUT forms .............. 73 3.7.3 BioID reveals that TENM4 interacts only with RARS and DARS MUTs ........ 74 3.8 GST-Purification of hPRS, RARS, and DARS WT and MUT proteins for Aminoacylation Assay ....................................................................................................... 75 Chapter 4: Discussion and Conclusion 4.1 Discussion .................................................................................................................... 89 4.2 Conclusion ................................................................................................................... 92 References ............................................................................................................................... 94 5 Abstract Hypomyelinating leukodystrophies (HLDs) are a genetically determined group of disorders characterized by deficient myelin deposition during development, which result in relatively specific clinical phenotypes. Recent findings in patients with clinical and radiological features consistent with an HLD have shown that this
Load more

Recommended publications
  • 1 Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental
    Page 1 of 255 Diabetes Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy Oliver J. Freeman1,2, Richard D. Unwin2,3, Andrew W. Dowsey2,3, Paul Begley2,3, Sumia Ali1, Katherine A. Hollywood2,3, Nitin Rustogi2,3, Rasmus S. Petersen1, Warwick B. Dunn2,3†, Garth J.S. Cooper2,3,4,5* & Natalie J. Gardiner1* 1 Faculty of Life Sciences, University of Manchester, UK 2 Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK 3 Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK 4 School of Biological Sciences, University of Auckland, New Zealand 5 Department of Pharmacology, Medical Sciences Division, University of Oxford, UK † Present address: School of Biosciences, University of Birmingham, UK *Joint corresponding authors: Natalie J. Gardiner and Garth J.S. Cooper Email: [email protected]; [email protected] Address: University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, United Kingdom Telephone: +44 161 275 5768; +44 161 701 0240 Word count: 4,490 Number of tables: 1, Number of figures: 6 Running title: Metabolic dysfunction in diabetic neuropathy 1 Diabetes Publish Ahead of Print, published online October 15, 2015 Diabetes Page 2 of 255 Abstract High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However our understanding of the molecular mechanisms which cause the marked distal pathology is incomplete. Here we performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN.
    [Show full text]
  • BOLA3 Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension
    BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Yu, Qiujun et al. “BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension.” Circulation 139 (2019): 2238-2255 © 2019 The Author(s) As Published https://dx.doi.org/10.1161/CIRCULATIONAHA.118.035889 Publisher Ovid Technologies (Wolters Kluwer Health) Version Author's final manuscript Citable link https://hdl.handle.net/1721.1/125622 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Circulation Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 May 07. Published in final edited form as: Circulation. 2019 May 07; 139(19): 2238–2255. doi:10.1161/CIRCULATIONAHA.118.035889. BOLA3 deficiency controls endothelial metabolism and glycine homeostasis in pulmonary hypertension Qiujun Yu, MD, PhD1, Yi-Yin Tai, MS1, Ying Tang, MS1, Jingsi Zhao, MS1, Vinny Negi, PhD1, Miranda K. Culley, BA1, Jyotsna Pilli, PhD1, Wei Sun, MD1, Karin Brugger, MD2, Johannes Mayr, MD2, Rajeev Saggar, MD3, Rajan Saggar, MD4, W. Dean Wallace, MD4, David J. Ross, MD4, Aaron B. Waxman, MD, PhD5, Stacy G. Wendell, PhD6,7, Steven J. Mullett, BS7, John Sembrat, BS1, Mauricio Rojas, MD1, Omar F. Khan, PhD8, James E. Dahlman, PhD9, Masataka Sugahara, MD1, Nobuyuki Kagiyama, MD1, Taijyu Satoh, MD1, Manling Zhang, MD, MS1, Ning Feng, MD, PhD1, John Gorcsan III, MD10, Sara O.
    [Show full text]
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • Investigation of the Underlying Hub Genes and Molexular Pathogensis in Gastric Cancer by Integrated Bioinformatic Analyses
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Investigation of the underlying hub genes and molexular pathogensis in gastric cancer by integrated bioinformatic analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The high mortality rate of gastric cancer (GC) is in part due to the absence of initial disclosure of its biomarkers. The recognition of important genes associated in GC is therefore recommended to advance clinical prognosis, diagnosis and and treatment outcomes. The current investigation used the microarray dataset GSE113255 RNA seq data from the Gene Expression Omnibus database to diagnose differentially expressed genes (DEGs). Pathway and gene ontology enrichment analyses were performed, and a proteinprotein interaction network, modules, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. Finally, validation of hub genes was performed. The 1008 DEGs identified consisted of 505 up regulated genes and 503 down regulated genes.
    [Show full text]
  • Teneurin 2 in Neuronal Network Formation 4699
    Development 129, 4697-4705 (2002) 4697 Printed in Great Britain © The Company of Biologists Limited 2002 DEV1819 Teneurin 2 is expressed by the neurons of the thalamofugal visual system in situ and promotes homophilic cell-cell adhesion in vitro Beatrix P. Rubin1,*, Richard P. Tucker2,*, Marianne Brown-Luedi1, Doris Martin1 and Ruth Chiquet-Ehrismann1,† 1Friedrich Miescher Institute, Novartis Research Foundation, PO Box 2543, CH-4002 Basel, Switzerland 2Department of Cell Biology and Human Anatomy, University of California at Davis, Davis, CA 95616, USA *These authors contributed equally to this work †Author for correspondence (e-mail: [email protected]) Accepted 20 June 2002 SUMMARY The transmembrane glycoprotein teneurin 2 is expressed domain of teneurin 2 by HT1080 cells induced cell by neurons in the developing avian thalamofugal visual aggregation, and the extracellular domain of teneurin 2 system at periods that correspond with target recognition became concentrated at sites of cell-cell contact in and synaptogenesis. Partial and full-length teneurin 2 neuroblastoma cells. These observations indicate that the constructs were expressed in cell lines in vitro. Expression homophilic binding of teneurin 2 may play a role in the of the cytoplasmic domain is required for the induction of development of specific neuronal circuits in the developing filopodia, the transport of teneurin 2 into neurites and visual system. the co-localization of teneurin 2 with the cortical actin cytoskeleton. In addition, expression of the extracellular Key words: DOC4, Neurestin, Odz, Tenm, Tena, Ten-m, Chicken INTRODUCTION in a signal transduction cascade, as mutational analysis showed that ten-m/odz is a member of the ‘pair-rule’ gene family and Teneurins are a family of type II transmembrane proteins has a central role in determining the segmentation of the originally discovered in Drosophila.
    [Show full text]
  • Proteolytically Released Lasso/Teneurin-2 Induces Axonal
    RESEARCH ARTICLE Proteolytically released Lasso/teneurin-2 induces axonal attraction by interacting with latrophilin-1 on axonal growth cones Nickolai V Vysokov1,2,3,4, John-Paul Silva2,5, Vera G Lelianova1,2, Jason Suckling2,6, John Cassidy2,7, Jennifer K Blackburn1,8, Natalia Yankova2,9, Mustafa BA Djamgoz2, Serguei V Kozlov10, Alexander G Tonevitsky11,12, Yuri A Ushkaryov1,2* 1School of Pharmacy, University of Kent, Chatham, United Kingdom; 2Department of Life Sciences, Imperial College London, London, United Kingdom; 3Wolfson Centre for Age Related Diseases, King’s College London, London, United Kingdom; 4BrainPatch Ltd, London, United Kingdom; 5Department of Bioanalytical Sciences, Non-clinical development, UCB-Pharma, Berkshire, United Kingdom; 6Thomsons Online Benefits, London, United Kingdom; 7Arix Bioscience, London, United Kingdom; 8Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, United States; 9Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, London, United Kingdom; 10Center for Advanced Preclinical Research, National Cancer Institute, Frederick, United States; 11Higher School of Economics, Moscow, Russia; 12Scientific Research Centre Bioclinicum, Moscow, Russia Abstract A presynaptic adhesion G-protein-coupled receptor, latrophilin-1, and a postsynaptic transmembrane protein, Lasso/teneurin-2, are implicated in trans-synaptic interaction that *For correspondence: Correspondence: y.ushkaryov@ contributes to synapse formation. Surprisingly, during neuronal development, a substantial kent.ac.uk proportion of Lasso is released into the intercellular space by regulated proteolysis, potentially precluding its function in synaptogenesis. We found that released Lasso binds to cell-surface Competing interest: See latrophilin-1 on axonal growth cones. Using microfluidic devices to create stable gradients of page 27 soluble Lasso, we show that it induces axonal attraction, without increasing neurite outgrowth.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • WO 2016/115632 Al 28 July 2016 (28.07.2016) W P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/115632 Al 28 July 2016 (28.07.2016) W P O P C T (51) International Patent Classification: (72) Inventors: TARNOPOLSKY, Mark; 309-397 King C12N 5/ 0 (2006.01) C12N 15/53 (2006.01) Street West, Dundas, Ontario L9H 1W9 (CA). SAFDAR, A61K 35/12 (2015.01) C12N 15/54 (2006.01) Adeel; c/o McMaster University, 1200 Main Street West, A61K 9/51 (2006.01) C12N 15/55 (2006.01) Hamilton, Ontario L8N 3Z5 (CA). C12N 15/11 (2006.01) C12N 15/85 (2006.01) (74) Agent: TANDAN, Susan; Gowling WLG (Canada) LLP, C12N 15/12 (2006.01) C12N 5/071 (2010.01) One Main Street West, Hamilton, Ontario L8P 4Z5 (CA). (21) International Application Number: (81) Designated States indicated, PCT/CA20 16/050046 (unless otherwise for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 2 1 January 2016 (21 .01 .2016) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/105,967 2 1 January 2015 (21.01.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/1 12,940 6 February 2015 (06.02.2015) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • Effects of EHP-101 on Inflammation and Remyelination in Murine Models
    Neurobiology of Disease 143 (2020) 104994 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Effects of EHP-101 on inflammation and remyelination in murine modelsof T Multiple sclerosis Carmen Navarretea, Adela García-Martinb, Martín Garrido-Rodríguezc,d,e, Leyre Mestref, ⁎ Ana Feliúf, Carmen Guazaf, Marco A. Calzadoc,d,e, Eduardo Muñozc,d,e, a Emerald Health Pharmaceuticals, San Diego, CA, USA b Emerald Health Biotechnology, Córdoba, Spain c Instituto Maimónides de Investigación Biomédica de Córdoba, Spain d Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Spain e Hospital Universitario Reina Sofía, Córdoba, Spain f Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal-CSIC, Madrid, Spain ARTICLE INFO ABSTRACT Keywords: Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in Multiple sclerosis the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in EHP-101 preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget Transcriptomic synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/ Inflammation Cannabinoid receptor type 2 (PPARγ/CB2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) Remyelination pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic, and neurodegenerative diseases. EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord.
    [Show full text]
  • Biological Models of Colorectal Cancer Metastasis and Tumor Suppression
    BIOLOGICAL MODELS OF COLORECTAL CANCER METASTASIS AND TUMOR SUPPRESSION PROVIDE MECHANISTIC INSIGHTS TO GUIDE PERSONALIZED CARE OF THE COLORECTAL CANCER PATIENT By Jesse Joshua Smith Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University In partial fulfillment of the requirements For the degree of DOCTOR OF PHILOSOPHY In Cell and Developmental Biology May, 2010 Nashville, Tennessee Approved: Professor R. Daniel Beauchamp Professor Robert J. Coffey Professor Mark deCaestecker Professor Ethan Lee Professor Steven K. Hanks Copyright 2010 by Jesse Joshua Smith All Rights Reserved To my grandparents, Gladys and A.L. Lyth and Juanda Ruth and J.E. Smith, fully supportive and never in doubt. To my amazing and enduring parents, Rebecca Lyth and Jesse E. Smith, Jr., always there for me. .my sure foundation. To Jeannine, Bill and Reagan for encouragement, patience, love, trust and a solid backing. To Granny George and Shawn for loving support and care. And To my beautiful wife, Kelly, My heart, soul and great love, Infinitely supportive, patient and graceful. ii ACKNOWLEDGEMENTS This work would not have been possible without the financial support of the Vanderbilt Medical Scientist Training Program through the Clinical and Translational Science Award (Clinical Investigator Track), the Society of University Surgeons-Ethicon Scholarship Fund and the Surgical Oncology T32 grant and the Vanderbilt Medical Center Section of Surgical Sciences and the Department of Surgical Oncology. I am especially indebted to Drs. R. Daniel Beauchamp, Chairman of the Section of Surgical Sciences, Dr. James R. Goldenring, Vice Chairman of Research of the Department of Surgery, Dr. Naji N.
    [Show full text]
  • Mitochondrial Genetics
    Mitochondrial genetics Patrick Francis Chinnery and Gavin Hudson* Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK Introduction: In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders. Sources of data: In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation. Areas of agreement: The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases. Areas of controversy: The exact mechanisms which govern the inheritance of mtDNA are hotly debated. Growing points: Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease. Keywords: mitochondria/genetics/mitochondrial DNA/mitochondrial disease/ mtDNA Accepted: April 16, 2013 Mitochondria *Correspondence address. The mitochondrion is a highly specialized organelle, present in almost all Institute of Genetic Medicine, International eukaryotic cells and principally charged with the production of cellular Centre for Life, Newcastle energy through oxidative phosphorylation (OXPHOS).
    [Show full text]
  • Biallelic Variants in HPDL Cause Pure and Complicated Hereditary Spastic Paraplegia
    doi:10.1093/brain/awab041 BRAIN 2021: Page 1 of 15 | 1 Downloaded from https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab041/6273093 by Motol Teaching Hospital user on 02 June 2021 Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia Manuela Wiessner,1,† Reza Maroofian,2,† Meng-Yuan Ni,3,† Andrea Pedroni,4,† Juliane S. Mu¨ller,5,6 Rolf Stucka,1 Christian Beetz,7 Stephanie Efthymiou,2 Filippo M. Santorelli,8 Ahmed A. Alfares,9 Changlian Zhu,10,11,12 Anna Uhrova Meszarosova,13 Elham Alehabib,14 Somayeh Bakhtiari,15 Andreas R. Janecke,16 Maria Gabriela Otero,17 Jin Yun Helen Chen,18 James T. Peterson,19 Tim M. Strom,20 Peter De Jonghe,21,22,23 Tine Deconinck,24 Willem De Ridder,21,22,23 Jonathan De Winter, 21,22,23 Rossella Pasquariello,8 Ivana Ricca,8 Majid Alfadhel,25 Bart P.van de Warrenburg,26,27 Ruben Portier,28 Carsten Bergmann,29 Saghar Ghasemi Firouzabadi,30 Sheng Chih Jin,31 Kaya Bilguvar,32,33 Sherifa Hamed,34 Mohammed Abdelhameed,34 Nourelhoda A. Haridy,2,34 Shazia Maqbool,35 Fatima Rahman,35 Najwa Anwar,35 Jenny Carmichael,36 Alistair Pagnamenta,37 Nick W. Wood,2,38 Frederic Tran Mau-Them,39 Tobias Haack,40 Genomics England Research Consortium, PREPARE network, Maja Di Rocco,41 Isabella Ceccherini,41 Michele Iacomino,41 Federico Zara,41,42 Vincenzo Salpietro,41,42 Marcello Scala,2 Marta Rusmini,41 Yiran Xu,10 Yinghong Wang,43 Yasuhiro Suzuki,44 Kishin Koh,45 Haitian Nan,45 Hiroyuki Ishiura,46 Shoji Tsuji,47 Lae¨titia Lambert,48 Emmanuelle Schmitt,49 Elodie Lacaze,50 Hanna Ku¨pper,51 David Dredge,18 Cara Skraban,52,53 Amy Goldstein,19,53 Mary J.
    [Show full text]