DOCSLIB.ORG

Thesis (Complete)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Thesis (Complete) UvA-DARE (Digital Academic Repository) Precision medicine in childhood asthma The role of genetic variations in treatment response Farzan, N. Publication date 2019 Document Version Final published version License Other Link to publication Citation for published version (APA): Farzan, N. (2019). Precision medicine in childhood asthma: The role of genetic variations in treatment response. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:04 Oct 2021 Precision Medicine in Childhood Asthma The role of genetic variations in treatment response Niloufar Farzan Precision Medicine in Childhood Asthma The role of genetic variations in treatment response Niloufar Farzan 1 Het printen van dit proefschrift werd mede mogelijk gemaakt door AMC Amsterdam en Longfonds (Lungfoundation Nertherlands). Printed by: Ipskamp Precision Medicine in Childhood Asthma: The role of genetic variations in treatment response 2019 Niloufar Farzan, Amsterdam. 2 Precision Medicine in Childhood Asthma The role of genetic variations in treatment response ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. ir. K.I.J. Maex ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op dinsdag 12 februari 2019, te 10.00 uur door Niloufar Farzan geboren te Tabriz 3 PROMOTIECOMMISSIE Promotor prof. dr. A.H. Maitland-van der Zee AMC-UvA Copromotor dr. S.J.H. Vijverberg AMC-UvA Overige leden: prof. dr. E.H.D. Bel AMC-UvA prof. dr. P.J. Sterk AMC-UvA dr. S.W.J. Terheggen AMC-UvA prof. dr. G. Bartlett-Esquilant McGill University, Montreal Canada prof. dr. B. Wilffert Rijksuniversiteit Groningen Faculteit der Geneeskunde 4 Table of contents Chapter 1: General introduction 7 Chapter 2: Reviewing evidence of (pharmaco)genomics effects in asthma 19 Chapter 2.1: The use of pharmacogenomics, epigenomics, and transcriptomics to improve 21 childhood asthma management: Where do we stand? Chapter 2.2: Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers: 45 a systematic review Chapter 3: Pharmacogenomics in childhood asthma 113 Chapter 3.1: Rationale and design of the multi-ethnic Pharmacogenomics in Childhood 115 Asthma Consortium Chapter 3.2: 17q21 variant increases risk of exacerbations in asthmatic children despite using 145 inhaled corticosteroids Chapter 3.3: Genome-wide association study of inhaled corticosteroid response in 171 African-admixed children with asthma Chapter 4: Risk factors associated with asthma exacerbations despite ICS use 213 Chapter 4.1: Risk factors of asthma exacerbations in asthmatic children treated with ICS: 215 is there an added value of genetic risk factors? Chapter 5: Cost-effectiveness of pharmacogenetic-guided treatment 251 Chapter 5.1: Cost-effectiveness of genotyping before starting LABA therapy in asthmatic 253 children and young adults. Chapter 6: General discussion 277 Scientific Summary & samenvatting 311 Appendices 326 5 6 CHAPTER 1 General Introduction 7 Evolution of disease management towards precision medicine Since prehistoric times, humans have used natural products such as extracts from plants, animals and even microorganisms to treat different diseases (1). However, only since the 19th century, pharmacology evolved as an independent principle when scientists began to develop and apply experiments to understand physiological mechanisms and drug actions (1). These advances were followed by the technological breakthroughs and development of synthetic techniques at the beginning of the 20th century which revolutionized the pharmaceutical industry (1). However, parallel to the development of highly effective pharmacological agents, evidence started to pile up regarding the inter- and intraindividual variability in response to most drugs (2). Studies show that response to most drugs ranges between 50 and 75 percent (2). This fact has triggered scientists to find out why an effective and safe medication for one group of patients has a decreased or an exaggerated effect in another group. Decades of research have shown that factors such as age (3), gender (4), diet (5) and concomitant disease or medication use (6) can influence response to treatment. Additionally, over the past three decades advances in genomic technologies have helped scientists discover the role of genomic variations in treatment response (7,8). Altogether, these findings indicated that a combination of clinical, environmental and genomic factors could result in treatment response heterogeneity. In fact, this idea has ultimately paved the way for a new era in medicine called Precision Medicine (9). According to National Institutes of Health (NIH), precision medicine is "an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person" (9). The ultimate aim of precision medicine is to increase health on the population level by preventing diseases and giving the right treatment to the right patient at the right time (9). Pharmacogenomics The study of the relation between variations in the genome and response to a specific medication in terms of efficacy and safety is called pharmacogenomics/pharmacogenetics (10). Although these two terms are used interchangeably, their definitions differ. Pharmacogenetics mainly refers to genes determining drug metabolism, pharmaco- genomics, on the other hand, studies all genes in the genome that might determine drug response (11). In this thesis, we will use the term pharmacogenomics. 8 Single Nucleotide Polymorphisms (SNPs), the most abundant genetic variations in the genome, are the most commonly investigated genetic variations in pharmacogenomics studies (12). A SNP is a single base pair change at a specific position in the DNA sequence that results in different alleles (12). The human genome contains approximately 10 million SNPs (13). SNPs can occur in both protein-coding and non-coding regions that might contain enhancers and promoters (13). SNPs that fall within the protein-coding regions might change the amino acid sequence which can subsequently result in an altered amount or function of the protein. SNPs within the non-coding regions may modify the expression of one or several genes (13). Any alterations in gene expression amount or function of the protein could ultimately influence the mechanisms related to absorption, distribution, metabolism or excretion/elimination (ADME) of the drug (pharmacokinetics) or target (mostly receptors) of the drugs (pharmacodynamics) (14). These alterations subsequently can influence the efficacy of the drug and treatment response (12,15). In pharmacogenomics studies, the association between genetic variations and treatment response is typically investigated by two main approaches: hypothesis-driven and hypothesis-generating approaches (16). The most common hypothesis-driven pharmaco- genomics studies are candidate gene studies (16). In these studies, ‘candidate genes’ are often selected based on prior knowledge of the biological mechanisms related to the disease or drug signaling pathway. The number of pre-selected SNPs can range from one to several hundred (16). In contrast to hypothesis-driven approaches, in hypothesis-generating approaches usually, thousands or even millions of SNPs are studied simultaneously without pre-selection (16). Hypothesis-generating approaches are suitable for identifying (novel) genetic markers in complex diseases and traits where not only genes but also environmental factors, gene- gene interactions, and gene-environment interactions play a role in the development of disease (17). Genome-Wide Association Studies (GWAS) are one of these high throughput methods that study 500,000 to millions of common SNPs (frequency 5%) across the genome (18). The SNPs that are not assayed on the genotyping chips, can be estimated using reference panels and based on the knowledge about the correlation between a large set of SNPs (linkage disequilibrium). This process which is called genotype imputation increases the number of common variants with great precision (17). The result of the pharmacogenomics studies could ultimately help to predict patients’ response to treatment based on their genetic makeup and could help to select the optimal drug and dose for each patient. Several clinical trials have shown promising results for 9 genotype-guided dosing algorithms of anticoagulants such as acenocoumarol, phencopromon, and warfarin (19,20) and genotype-guided drug selection for carbamazepine (an anti-epileptic drug) (21) and abacavir (an antiretroviral drug) (22). Pharmacogenomic
Load more

Recommended publications
  • Functional Characterization of the New 8Q21 Asthma Risk Locus
    Functional characterization of the new 8q21 Asthma risk locus Cristina M T Vicente B.Sc, M.Sc A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2017 Faculty of Medicine Abstract Genome wide association studies (GWAS) provide a powerful tool to identify genetic variants associated with asthma risk. However, the target genes for many allergy risk variants discovered to date are unknown. In a recent GWAS, Ferreira et al. identified a new association between asthma risk and common variants located on chromosome 8q21. The overarching aim of this thesis was to elucidate the biological mechanisms underlying this association. Specifically, the goals of this study were to identify the gene(s) underlying the observed association and to study their contribution to asthma pathophysiology. Using genetic data from the 1000 Genomes Project, we first identified 118 variants in linkage disequilibrium (LD; r2>0.6) with the sentinel allergy risk SNP (rs7009110) on chromosome 8q21. Of these, 35 were found to overlap one of four Putative Regulatory Elements (PREs) identified in this region in a lymphoblastoid cell line (LCL), based on epigenetic marks measured by the ENCODE project. Results from analysis of gene expression data generated for LCLs (n=373) by the Geuvadis consortium indicated that rs7009110 is associated with the expression of only one nearby gene: PAG1 - located 732 kb away. PAG1 encodes a transmembrane adaptor protein localized to lipid rafts, which is highly expressed in immune cells. Results from chromosome conformation capture (3C) experiments showed that PREs in the region of association physically interacted with the promoter of PAG1.
    [Show full text]
  • 1 INVITED REVIEW Mechanisms of Gasdermin Family Members in Inflammasome Signaling and Cell Death Shouya Feng,* Daniel Fox,* Si M
    INVITED REVIEW Mechanisms of Gasdermin family members in inflammasome signaling and cell death Shouya Feng,* Daniel Fox,* Si Ming Man Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia. * S.F. and D.F. equally contributed to this work Correspondence to Si Ming Man: Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, 2601, Australia. [email protected] 1 Abstract The Gasdermin (GSDM) family consists of Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD), Gasdermin E (GSDME) and Pejvakin (PJVK). GSDMD is activated by inflammasome-associated inflammatory caspases. Cleavage of GSDMD by human or mouse caspase-1, human caspase-4, human caspase-5, and mouse caspase-11, liberates the N-terminal effector domain from the C-terminal inhibitory domain. The N-terminal domain oligomerizes in the cell membrane and forms a pore of 10-16 nm in diameter, through which substrates of a smaller diameter, such as interleukin (IL)-1β and IL- 18, are secreted. The increasing abundance of membrane pores ultimately leads to membrane rupture and pyroptosis, releasing the entire cellular content. Other than GSDMD, the N-terminal domain of all GSDMs, with the exception of PJVK, have the ability to form pores. There is evidence to suggest that GSDMB and GSDME are cleaved by apoptotic caspases. Here, we review the mechanistic functions of GSDM proteins with respect to their expression and signaling profile in the cell, with more focused discussions on inflammasome activation and cell death.
    [Show full text]
  • Gene Expression Profile of THP-1 Cells Treated with Heat-Killed Candida Albicans
    Original Article Page 1 of 5 Gene expression profile of THP-1 cells treated with heat-killed Candida albicans Zhi-De Hu1,2*, Ting-Ting Wei1*, Qing-Qin Tang1, Ning Ma1, Li-Li Wang1, Bao-Dong Qin1, Jian-Rong Yin1, Lin Zhou1, Ren-Qian Zhong1 1Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 2Department of Laboratory Medicine, General Hospital, Ji’nan Military Region of PLA, Ji’nan 250031, China Contributions: (I) Conception and design: RQ Zhong, L Zhou, ZD Hu; (II) Administrative support: RQ Zhong; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. *These authors contributed equally to this work. Correspondence to: Ren-Qian Zhong, MD, PhD. Department of Laboratory Medicine, Changzheng Hospital, the Second Military Medical University, Shanghai 200003, China. Email: [email protected]; Lin Zhou, MD, PhD. Department of Laboratory Medicine, Changzheng Hospital, the Second Military Medical University, Shanghai 200003, China. Email: [email protected]. Background: Mechanisms under immune response against Candida albicans (C. albicans) remain largely unknown. To better understand the mechanisms of innate immune response against C. albicans, we analyzed the gene expression profile of THP-1 cells stimulated with heat-killed C. albicans. Methods: THP-1 cells were stimulated with heat-killed C. albicans for 9 hours at a ratio of 1:1, and gene expression profile of the cells was analyzed using Whole Human Genome Oligo Microarray. Differentially expressed genes were defined as change folds more than 2 and with statistical significance.
    [Show full text]
  • Agricultural University of Athens
    ΓΕΩΠΟΝΙΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΣΧΟΛΗ ΕΠΙΣΤΗΜΩΝ ΤΩΝ ΖΩΩΝ ΤΜΗΜΑ ΕΠΙΣΤΗΜΗΣ ΖΩΙΚΗΣ ΠΑΡΑΓΩΓΗΣ ΕΡΓΑΣΤΗΡΙΟ ΓΕΝΙΚΗΣ ΚΑΙ ΕΙΔΙΚΗΣ ΖΩΟΤΕΧΝΙΑΣ ΔΙΔΑΚΤΟΡΙΚΗ ΔΙΑΤΡΙΒΗ Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων ΕΙΡΗΝΗ Κ. ΤΑΡΣΑΝΗ ΕΠΙΒΛΕΠΩΝ ΚΑΘΗΓΗΤΗΣ: ΑΝΤΩΝΙΟΣ ΚΟΜΙΝΑΚΗΣ ΑΘΗΝΑ 2020 ΔΙΔΑΚΤΟΡΙΚΗ ΔΙΑΤΡΙΒΗ Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων Genome-wide association analysis and gene network analysis for (re)production traits in commercial broilers ΕΙΡΗΝΗ Κ. ΤΑΡΣΑΝΗ ΕΠΙΒΛΕΠΩΝ ΚΑΘΗΓΗΤΗΣ: ΑΝΤΩΝΙΟΣ ΚΟΜΙΝΑΚΗΣ Τριμελής Επιτροπή: Aντώνιος Κομινάκης (Αν. Καθ. ΓΠΑ) Ανδρέας Κράνης (Eρευν. B, Παν. Εδιμβούργου) Αριάδνη Χάγερ (Επ. Καθ. ΓΠΑ) Επταμελής εξεταστική επιτροπή: Aντώνιος Κομινάκης (Αν. Καθ. ΓΠΑ) Ανδρέας Κράνης (Eρευν. B, Παν. Εδιμβούργου) Αριάδνη Χάγερ (Επ. Καθ. ΓΠΑ) Πηνελόπη Μπεμπέλη (Καθ. ΓΠΑ) Δημήτριος Βλαχάκης (Επ. Καθ. ΓΠΑ) Ευάγγελος Ζωίδης (Επ.Καθ. ΓΠΑ) Γεώργιος Θεοδώρου (Επ.Καθ. ΓΠΑ) 2 Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων Περίληψη Σκοπός της παρούσας διδακτορικής διατριβής ήταν ο εντοπισμός γενετικών δεικτών και υποψηφίων γονιδίων που εμπλέκονται στο γενετικό έλεγχο δύο τυπικών πολυγονιδιακών ιδιοτήτων σε κρεοπαραγωγικά ορνίθια. Μία ιδιότητα σχετίζεται με την ανάπτυξη (σωματικό βάρος στις 35 ημέρες, ΣΒ) και η άλλη με την αναπαραγωγική
    [Show full text]
  • Genetic Variation and Functional Analysis of the Cardiomedin Gene
    TECHNISCHE UNIVERSITÄT MÜNCHEN LEHRSTUHL FÜR EXPERIMENTELLE GENETIK Genetic Variation and Functional Analysis of the Cardiomedin Gene Zasie Susanne Schäfer Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzende: Univ.-Prof. A. Schnieke, Ph.D. Prüfer der Dissertation: 1. apl. Prof. Dr. J. Adamski 2. Univ.-Prof. Dr. Dr. H.-R. Fries 3. Univ.-Prof. Dr. Th. Meitinger Die Dissertation wurde am. 31.05.2011 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 02.04.2012 angenommen. Table of Contents Table of contents Abbreviations ........................................................................................................................ 7 1. Summary ..........................................................................................................................10 Zusammenfassung ...............................................................................................................11 2. Introduction ......................................................................................................................12 2.1 Genome-wide association studies (GWAS) and post-GWAS functional genomics ......12 2.2 Genetic influences on cardiac repolarization and sudden cardiac death syndrome in GWAS and the chromosome
    [Show full text]
  • Autocrine IFN Signaling Inducing Profibrotic Fibroblast Responses by a Synthetic TLR3 Ligand Mitigates
    Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021 Inducing is online at: average * The Journal of Immunology published online 16 August 2013 from submission to initial decision 4 weeks from acceptance to publication http://www.jimmunol.org/content/early/2013/08/16/jimmun ol.1300376 A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Autocrine IFN Signaling Feng Fang, Kohtaro Ooka, Xiaoyong Sun, Ruchi Shah, Swati Bhattacharyya, Jun Wei and John Varga J Immunol Submit online. Every submission reviewed by practicing scientists ? is published twice each month by http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.130037 6.DC1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 28, 2021. Published August 16, 2013, doi:10.4049/jimmunol.1300376 The Journal of Immunology A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Inducing Autocrine IFN Signaling Feng Fang,* Kohtaro Ooka,* Xiaoyong Sun,† Ruchi Shah,* Swati Bhattacharyya,* Jun Wei,* and John Varga* Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN.
    [Show full text]
  • The Gasdermins, a Protein Family Executing Cell Death And
    1 Title: 2 The gasdermins, a protein family executing cell death and inflammation 3 4 Authors: Petr Broz1, Pablo Pelegrín2 and Feng Shao3 5 6 1 Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland. 7 2 Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital "Virgen de la 8 Arrixaca", Murcia 30120, Spain. 9 3 National Institute of Biological Sciences, Beijing 102206, China 10 11 12 Correspondence to P.B. [email protected]; P.P. [email protected]; F.S. [email protected] 13 14 15 Preface: (102 out of max 100 words) 16 17 The gasdermins are a new family of pore-forming cell death effectors that cause membrane 18 permeabilization and pyroptosis, a lytic pro-inflammatory type of cell death. Gasdermins consist of a 19 cytotoxic N-terminal domain and a C-terminal repressor domain connected by a flexible linker. 20 Proteolytic cleavage between these two domains releases the intramolecular inhibition on the cytotoxic 21 domain, allowing it to insert into cell membranes and to form large oligomeric membrane pores, which 22 disrupt ion homeostasis and induce cell death. In this review, we discuss the recent developments in 23 gasdermin research with a focus on the mechanisms that control gasdermin activation, pore formation 24 and the consequences of gasdermin-induced membrane permeabilization. 25 26 1 27 28 Key points (list max 6) 29 30 • The gasdermins are evolutionary conserved family of cell death effectors, which 31 comprises 6 members (gasdermin A, B, C, D, E and Pejvakin) in humans and 10 members in 32 mice (gasdermin A1-3, C1-4, D, E and PJVK).
    [Show full text]
  • Identification and Mechanistic Investigation of Recurrent Functional Genomic and Transcriptional Alterations in Advanced Prostat
    Identification and Mechanistic Investigation of Recurrent Functional Genomic and Transcriptional Alterations in Advanced Prostate Cancer Thomas A. White A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2013 Reading Committee: Peter S. Nelson, Chair Janet L. Stanford Raymond J. Monnat Jay A. Shendure Program Authorized to Offer Degree: Molecular and Cellular Biology ©Copyright 2013 Thomas A. White University of Washington Abstract Identification and Mechanistic Investigation of Recurrent Functional Genomic and Transcriptional Alterations in Advanced Prostate Cancer Thomas A. White Chair of the Supervisory Committee: Peter S. Nelson, MD Novel functionally altered transcripts may be recurrent in prostate cancer (PCa) and may underlie lethal and advanced disease and the neuroendocrine small cell carcinoma (SCC) phenotype. We conducted an RNASeq survey of the LuCaP series of 24 PCa xenograft tumors from 19 men, and validated observations on metastatic tumors and PCa cell lines. Key findings include discovery and validation of 40 novel fusion transcripts including one recurrent chimera, many SCC-specific and castration resistance (CR) -specific novel splice isoforms, new observations on SCC-specific and TMPRSS2-ERG specific differential expression, the allele-specific expression of certain recurrent non- synonymous somatic single nucleotide variants (nsSNVs) previously discovered via exome sequencing of the same tumors, rgw ubiquitous A-to-I RNA editing of base excision repair (BER) gene NEIL1 as well as CDK13, a kinase involved in RNA splicing, and the SCC expression of a previously unannotated long noncoding RNA (lncRNA) at Chr6p22.2. Mechanistic investigation of the novel lncRNA indicates expression is regulated by derepression by master neuroendocrine regulator RE1-silencing transcription factor (REST), and may regulate some genes of axonogenesis and angiogenesis.
    [Show full text]
  • Members of a Novel Gene Family, Gsdm, Are Expressed Exclusively in the Epithelium of the Skin and Gastrointestinal Tract in a Highly Tissue-Specific Manner☆
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Genomics 89 (2007) 618–629 www.elsevier.com/locate/ygeno Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner☆ Masaru Tamura a,b,1, Shigekazu Tanaka a,b,1, Tomoaki Fujii a,b,1, Aya Aoki c, Hiromitu Komiyama a,d, Kiyoshi Ezawa e, Kenta Sumiyama e, ⁎ Tomoko Sagai a, Toshihiko Shiroishi a,b, a Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-0845, Japan b Department of Genetics, School of Life Science, The Graduate University for Advanced Studies, 1111 Yata, Mishima, Shizuoka 411-0845, Japan c Department of Neurosurgery, Juntendo University School of Medicine, Shizuoka Hospital, 1129 Nagaoka, Izunagaoka-chou, Izunokuni, Shizuoka 410-2295, Japan d Department of Coloproctological Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan e Division of Population Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-0845, Japan Received 5 September 2006; accepted 8 January 2007 Available online 12 March 2007 Abstract Gasdermin (Gsdm) was originally identified as a candidate causative gene for several mouse skin mutants. Several Gsdm-related genes sharing a protein domain with DFNA5, the causative gene of human nonsyndromic hearing loss, have been found in the mouse and human genomes, and this group is referred to as the DFNA5–Gasdermin domain family. However, our current comparative genomic analysis identified several novel motifs distinct from the previously reported domain in the Gsdm-related genes.
    [Show full text]
  • Gasdermin (H-6): Sc-376318
    SANTA CRUZ BIOTECHNOLOGY, INC. gasdermin (H-6): sc-376318 BACKGROUND APPLICATIONS Gasdermin, also known as GSDMA, GSDM or FKSG9, is a 445 amino acid gasdermin (H-6) is recommended for detection of gasdermin A of mouse, protein that localizes to the perinuclear region of the cytoplasm and belongs rat and human origin by Western Blotting (starting dilution 1:100, dilution to the gasdermin family. Expressed predominately in tissues of the gastroin- range 1:100-1:1000), immunoprecipitation [1-2 µg per 100-500 µg of total testinal tract and also present in skin and mammary gland, gasdermin func- protein (1 ml of cell lysate)], immunofluorescence (starting dilution 1:50, tions to induce apoptosis and is thought to possess tumor suppression activity, dilution range 1:50-1:500) and solid phase ELISA (starting dilution 1:30, specifically in gastric cancer cells. The gene encoding gasdermin maps to dilution range 1:30-1:3000). human chromosome 17, which comprises over 2.5% of the human genome Suitable for use as control antibody for gasdermin siRNA (h): sc-75109, and encodes over 1,200 genes. Two key tumor suppressor genes are associ- gasdermin siRNA (m): sc-75110, gasdermin shRNA Plasmid (h): sc-75109-SH, ated with chromosome 17, namely, p53 and BRCA1. Tumor suppressor p53 is gasdermin shRNA Plasmid (m): sc-75110-SH, gasdermin shRNA (h) Lentiviral necessary for maintenance of cellular genetic integrity by moderating cell fate Particles: sc-75109-V and gasdermin shRNA (m) Lentiviral Particles: through DNA repair versus cell death. Malfunction or loss of p53 expression is sc-75110-V.
    [Show full text]
  • Fakultät Für Medizin Der Technischen Universität
    _______________________________________________________________________________ (Name der promotionsführenden Einrichtung) _______________________________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ (Titel der wissenschaftlichen Abhandlung) _______________________________________________________________________________ (Vor- und Nachname) Vollständiger Abdruck der von der promotionsführenden Einrichtung _______________________________________________________________________________ der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors __________________________________________________________________ genehmigten Dissertation. Vorsitzender: _________________________________________________________________ Prüfer der Dissertation: 1. __________________________________________________________________________ 2. _________________________________________________________________________ 3. _________________________________________________________________________ Die Dissertation wurde ______________________________ bei der Technischen Universität München eingereicht und durch die promotionsführende Einrichtung __________________________________________________________________ angenommen. !1 Table of contents Table of contents Table of contents 2 Abbreviations 4 Summary 5 1 Introduction: 7 1.1 Analytical studies in genetic epidemiology (Asthma) 7
    [Show full text]
  • Wan, Yize Isalina (2011) Genetic Epidemiology of Atopy and Asthma
    Wan, Yize Isalina (2011) Genetic epidemiology of atopy and asthma. PhD thesis, University of Nottingham. Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/12224/1/Print_YWan_ThesisFinal_Oct2011.pdf Copyright and reuse: The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. · Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. · To the extent reasonable and practicable the material made available in Nottingham ePrints has been checked for eligibility before being made available. · Copies of full items can be used for personal research or study, educational, or not- for-profit purposes without prior permission or charge provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. · Quotations or similar reproductions must be sufficiently acknowledged. Please see our full end user licence at: http://eprints.nottingham.ac.uk/end_user_agreement.pdf A note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. For more information, please contact [email protected] Genetic Epidemiology of Atopy and Asthma By Yize I Wan, BMedsci. (Hons) Thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy May 2011 To my family, with all my love Contents ABSTRACT ..........................................................................................................................I ACKNOWLEDGEMENTS ...............................................................................................
    [Show full text]