DOCSLIB.ORG

Calcium Homeostasis Modulator (CALHM1/2) in Pulmonary Arterial Hypertension

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Calcium Homeostasis Modulator (CALHM1/2) in Pulmonary Arterial Hypertension Calcium Homeostasis Modulator (CALHM1/2) in Pulmonary Arterial Hypertension Item Type text; Electronic Thesis Authors Rodriguez, Marisela Citation Rodriguez, Marisela. (2020). Calcium Homeostasis Modulator (CALHM1/2) in Pulmonary Arterial Hypertension (Master's thesis, University of Arizona, Tucson, USA). Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 27/09/2021 03:13:25 Link to Item http://hdl.handle.net/10150/648659 CALCIUM HOMEOSTASIS MODULATOR (CALHM1/2) IN PULMONARY ARTERIAL HYPERTENSION By Marisela Rodriguez Copyright © Marisela Rodriguez 2020 A Thesis Submitted to the Faculty of the COLLEGE OF MEDICINE In Partial Fulfillment of the Requirements For the Degree of MASTER OF SCIENCE WITH A MAJOR IN CLINICAL TRANSLATIONAL SCIENCES In the Graduate College THE UNIVERSITY OF ARIZONA 2020 - 2 - Acknowledgements I would like to acknowledge the members of the Yuan Lab throughout my undergraduate years who inspired me to join research, taught me what it means to be a part of the scientific community, and always showed support for a young student as myself. It has led me to pursue a graduate education in this field and continue as a part of the scientific investigatory community. I would like to thank my thesis committee for their advising and support. Dr. Jiyuan Chen (Era) for contributing and expanding this project with me. I would also like to thank my mentor, Professor Jason Yuan for his patience and teachings, never having a direct way of saying things but allowing for the message to be said in parables and applicable to everything in life. Also, for always reminding me that there are three factors to my work- heart, brain, and hands. - 3 - Dedication This work is dedicated to my family and friends for their unconditional support, encouragement, and belief in me; especially my father for always setting standards and my mother for advising on hard work ethic and both reminding me to implement my all into everything I do. - 4 - TABLE OF CONTENTS LIST OF FIGURES ................................................................................................................................. - 6 - LIST OF TABLES ................................................................................................................................... - 7 - LIST OF ABBREVIATIONS AND ACRONYMS: ................................................................................ - 8 - ABSTRACT .......................................................................................................................................... - 11 - SIGNIFICANCE AND INTRODUCTION ........................................................................................... - 15 - PHENOTYPICAL SWITCH AND PAH .............................................................................................. - 27 - ION CHANNELS AND PULMONARY HYPERTENSION ............................................................... - 33 - CALCIUM HOMEOSTASIS MODULATOR ...................................................................................... - 38 - MATERIALS AND METHODS ........................................................................................................... - 47 - Pulmonary Artery Isolation ................................................................................................................... - 47 - Isolation and preparation of rat PASMC ............................................................................................... - 47 - Western Blotting .................................................................................................................................... - 54 - Polymerase Chain Reaction ................................................................................................................... - 60 - Statistical Analysis ................................................................................................................................. - 65 - RESULTS .............................................................................................................................................. - 66 - CONCLUSION ...................................................................................................................................... - 83 - REFERENCES ...................................................................................................................................... - 86 - - 5 - LIST OF FIGURES Figure 1 – Treatment algorithm of pulmonary arterial hypertension ……………………. 21 Figure 2 – Immunoflourescent staining of human SMCs………………………………... 27 Figure 3 – PASMC Phenotypic Plasticity………………………………………………… 29 Figure 4 – Mechanisms and signaling cascade of Ca2+ in PAH………………………...... 34 Figure 5 – Crystal structure images of human CALHM2 dimer…………………………. 36 Figure 6 – Transmembrane topology of CALHM channel………………………………. 38 Figure 7 – CALHM 1-3 mRNA expression level………………………………………... 42 Figure 8 – Freshly isolated PA branches from rat………………………………………... 49 Figure 9 – Primary PASMC Isolation Steps……………………………………………... 50 Figure 10 – Contractile vs proliferative phenotype markers…………………………….. 64 Figure 11 – Upregulated CALHM1 and 2……………………………………………….. 66 Figure 12 – Upregulated AKT/mTOR signaling proteins……………………………….. 68 Figure 13 – CaSR and Notch upregulated in phenotypical transition……………………. 71 Figure 14 – Pulmonary vascular remodeling in chronic hypoxia………………………… 74 Figure 15 – Rapamycin downregulates CALHM1 and 2………………………………… 77 Figure 16 – Upregulated CALHM1 and 2 in MCT………………………………………. 79 Figure 17 – Upregulated CALHM1 in IPAH hPASMCs………………………………… 79 - 6 - LIST OF TABLES Table 1 – Hemodynamic definition of pulmonary hypertension (PH)…………………… 13 Table 2 – Clinical classification of pulmonary hypertension (PH)………………………. 15 Table 3 – Female to male ratios in major PAH registries………………………………… 18 Table 4 – Drugs approved by FDA to treat PAH…………………………………………. 20 Table 5 – Contractile and proliferative SMC markers…………………………………… 26 Table 6 – CALHM 1-3 PCR primer sequences………………………………………….. 43 - 7 - LIST OF ABBREVIATIONS AND ACRONYMS: ACTA2 Smooth muscle cell actin ANG-1 Angiopoietin-1 AVD Apoptotic volume decrease 2+ 2+ [Ca ]cyt Cytosolic free Ca concentration CALHM Calcium homeostasis modulator Came calmodulin CaSR Calcium-sensing receptor CCE Capacitive Ca2+ entry CO Cardiac Output CO2 Carbon dioxide CpcPH Combined pre-and post-capillary PH CREB cAMP response element binding protein CTEPH Chronic thromboembolic pulmonary hypertension DAG Diacylglycerol EC-coupling Excitation-contraction coupling ECM Extracellular matrix ER Endoplasmic reticulum FBS Fetal bovine serum FGFR Fibroblast growth factor receptor GPCR G protein-coupled receptor HIF-1α Hypoxia-inducible factor 1α HIV Human immunodeficiency virus HPV Hypoxic pulmonary vasoconstriction IH Intimal hyperplasia inh. Inhalation IP3 Inositol 1,4,5-triphosphate IpcPH Isolated post-capillary PH i.v. Intravenous injection LVEF Left ventricle ejection fraction - 8 - MAPK Mitogen-activated protein kinase pathway MHC11 Myosin heavy chain-11 MLCK Myosin light chain kinase mPAP Mean pulmonary arterial pressure mmHg Millimeters mercury NFAT Nuclear factor of activated T-cells NO Nitric oxide NYHA-FC New York Heart Association Functional Classification PA Pulmonary artery PASMC Pulmonary artery smooth muscle cell PAP Pulmonary arterial pressure PAH Pulmonary arterial hypertension PAWP Pulmonary arterial wedge pressure PCH Pulmonary capillary hemangiomatosis PDGF Platelet-derived growth factor PGI2 Prostacyclin PH Pulmonary hypertension PM Plasma membrane p.o. Oral administration PVOD Pulmonary vino-occlusive disease PVR Pulmonary vascular resistance REVEAL Registry to Evaluate Early and Long-term PAH disease management RHC Right heart catheterization ROCC Receptor-operated Ca2+ channel ROCE Receptor-operated Ca2+ entry ROS Reactive oxygen species RTK Receptor tyrosine kinase RV Right ventricle SMC Smooth muscle cell SOCC Store-operated Ca2+ channel SOCE Store-operated Ca2+ entry s.q. Subcutaneous injection - 9 - SR Sarcoplasmic reticulum STIM Stromal interaction molecule TKR Tyrosine kinase receptor TRPC transient receptor potential channel VDCC Voltage-dependent Ca2+ channel VSMC Vascular smooth muscle cell WHO-FC World health organization functional classification WSPH World Symposium on Pulmonary Hypertension WU Wood Units - 10 - ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that predominantly affects women. The increased pulmonary arterial pressure (PAP) in patients with PAH is mainly generated by increased pulmonary vascular resistance (PVR) (18, 70, 103). Sustained pulmonary vasoconstriction, excessive pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular wall stiffness are the major causes for the elevated PVR and PAP in patients with PAH. Concentric pulmonary vascular remodeling is among one of the major causes for the elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP), also one the major causes for increasing afterload of right ventricle (RV) and inducing right heart failure leading to death if untreated (103). Excessive pulmonary artery smooth muscle cell (PASMC) proliferation and inhibited PASMC apoptosis have been implicated
Load more

Recommended publications
  • Salty Taste Deficits in CALHM1 Knockout Mice M
    Donald and Barbara Zucker School of Medicine Journal Articles Academic Works 2014 Salty Taste Deficits in CALHM1 Knockout Mice M. G. Tordoff H. T. Ellis T. R. Aleman A. Downing P. Marambaud Northwell Health See next page for additional authors Follow this and additional works at: https://academicworks.medicine.hofstra.edu/articles Part of the Medical Molecular Biology Commons Recommended Citation Tordoff M, Ellis H, Aleman T, Downing A, Marambaud P, Foskett ,J Dana R, McCaughey S. Salty Taste Deficits in CALHM1 Knockout Mice. 2014 Jan 01; 39(6):Article 2870 [ p.]. Available from: https://academicworks.medicine.hofstra.edu/articles/2870. Free full text article. This Article is brought to you for free and open access by Donald and Barbara Zucker School of Medicine Academic Works. It has been accepted for inclusion in Journal Articles by an authorized administrator of Donald and Barbara Zucker School of Medicine Academic Works. For more information, please contact [email protected]. Authors M. G. Tordoff, H. T. Ellis, T. R. Aleman, A. Downing, P. Marambaud, J. K. Foskett, R. M. Dana, and S. A. McCaughey This article is available at Donald and Barbara Zucker School of Medicine Academic Works: https://academicworks.medicine.hofstra.edu/articles/2870 Chem. Senses 39: 515–528, 2014 doi:10.1093/chemse/bju020 Advance Access publication May 20, 2014 Salty Taste Deficits in CALHM1 Knockout Mice Michael G. Tordoff1, Hillary T. Ellis1, Tiffany R. Aleman1, Arnelle Downing1, Philippe Marambaud2, J. Kevin Foskett3, Rachel M. Dana4 and Stuart
    [Show full text]
  • Anti-CALHM1 Antibody (ARG56385)
    Product datasheet [email protected] ARG56385 Package: 100 μl anti-CALHM1 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes CALHM1 Tested Reactivity Hu, Rat Tested Application IHC-P, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name CALHM1 Antigen Species Human Immunogen Recombinant protein of Human CALHM1 Conjugation Un-conjugated Alternate Names FAM26C; Calcium homeostasis modulator protein 1; Protein FAM26C Application Instructions Application table Application Dilution IHC-P 1:50 - 1:200 WB 1:500 - 1:2000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control SH-SY5Y Calculated Mw 38 kDa Properties Form Liquid Purification Affinity purification with immunogen. Buffer PBS (pH 7.3), 0.02% Sodium azide and 50% Glycerol. Preservative 0.02% sodium azide Stabilizer 50% Glycerol Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. www.arigobio.com 1/2 Bioinformation Database links GeneID: 255022 Human Swiss-port # Q8IU99 Human Gene Symbol CALHM1 Gene Full Name calcium homeostasis modulator 1 Background This gene encodes a calcium channel that plays a role in processing of amyloid-beta precursor protein. A polymorphism at this locus has been reported to be associated with susceptibility to late-onset Alzheimer's disease in some populations, but the pathogenicity of this polymorphism is unclear.[provided by RefSeq, Mar 2010] Function Pore-forming subunit of a voltage-gated ion channel required for sensory perception of sweet, bitter and umami tastes.
    [Show full text]
  • Network and Pathway-Based Analysis of Single-Nucleotide Polymorphism of Mirna in Temporal Lobe Epilepsy
    Molecular Neurobiology (2019) 56:7022–7031 https://doi.org/10.1007/s12035-019-1584-4 Network and Pathway-Based Analysis of Single-Nucleotide Polymorphism of miRNA in Temporal Lobe Epilepsy Wenbiao Xiao1 & Yanhao Wu2 & Jianjian Wang3 & Zhaohui Luo1 & Lili Long1 & Na Deng1 & Shangwei Ning4 & Yi Zeng5 & Hongyu Long1 & Bo Xiao1 Received: 18 September 2018 /Accepted: 21 March 2019 /Published online: 9 April 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Temporal lobe epilepsy (TLE) is a complex disease with its pathogenetic mechanism still unclear. Single-nucleotide polymor- phisms (SNPs) of miRNA (miRSNPs) are SNPs located on miRNA genes or target sites of miRNAs, which have been proved to be associated with neuropsychic disease development by interfering with miRNA-mediated regulatory function. In this study, we integrated TLE–related risk genes and risk pathways multi-dimensionally based on public data resources. Furthermore, we systematically screened candidate functional miRSNPs for TLE and constructed a TLE-associated pathway-based miRSNP switching network, which included 92 miRNAs that target 12 TLE risk pathways. Moreover, we dissected thoroughly the correlation between 5 risk genes of 4 risk pathways and TLE development. Additionally, the biological function of several candidate miRSNPs were validated by luciferase reporter assay. In silico approach facilitates to select potential BmiRSNP- miRNA-risk gene-pathway^ axis for experimental validation, which provided new insights into the mechanism of
    [Show full text]
  • Universidade De São Paulo Faculdade De Zootecnia E Engenharia De Alimentos
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE ZOOTECNIA E ENGENHARIA DE ALIMENTOS LAÍS GRIGOLETTO Genomic studies in Montana Tropical Composite cattle Pirassununga 2020 LAIS GRIGOLETTO Genomic studies in Montana Tropical Composite cattle Versão Corrigida Thesis submitted to the College of Animal Science and Food Engineering, University of São Paulo in partial fulfillment of the requirements for the degree of Doctor in Science from the Animal Biosciences program. Concentration area: Genetics, Molecular and Cellular Biology Supervisor: Prof. Dr. José Bento Sterman Ferraz Co-supervisor: Prof. Dr. Fernando Baldi Pirassununga 2020 Ficha catalográfica elaborada pelo Serviço de Biblioteca e Informação, FZEA/USP, com os dados fornecidos pelo(a) autor(a) Grigoletto, Laís G857g Genomic studies in Montana Tropical Composite cattle / Laís Grigoletto ; orientador José Bento Sterman Ferraz ; coorientador Fernando Baldi. -- Pirassununga, 2020. 183 f. Tese (Doutorado - Programa de Pós-Graduação em Biociência Animal) -- Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo. 1. beef cattle. 2. composite. 3. genomics. 4. imputation. 5. genetic progress. I. Ferraz, José Bento Sterman, orient. II. Baldi, Fernando, coorient. III. Título. Permitida a cópia total ou parcial deste documento, desde que citada a fonte - o autor UNIVERSIDADE DE SÃO PAULO Faculdade de Zootecnia e Engenharia de Alimentos Comissão de Ética no Uso de Animais DISPENSA DE ANÁLISE ÉTICA Comunicamos que o projeto de pesquisa abaixo identificado está dispensado da análise ética por utilizar animais oriundos de coleções biológicas formadas anteriormente ao ano de 2008, ano da promulgação da Lei nº 11.794/2008 – lei que estabelece procedimentos para o uso científico de animais. Ressaltamos que atividades realizadas na vigência da referida lei, ou que resulte em incremento do acervo biológico, devem ser submetidas à análise desta CEUA conforme disposto pelo Conselho Nacional de Controle de Experimentação Animal (CONCEA).
    [Show full text]
  • Identification of Novel Regulatory Genes in Acetaminophen
    IDENTIFICATION OF NOVEL REGULATORY GENES IN ACETAMINOPHEN INDUCED HEPATOCYTE TOXICITY BY A GENOME-WIDE CRISPR/CAS9 SCREEN A THESIS IN Cell Biology and Biophysics and Bioinformatics Presented to the Faculty of the University of Missouri-Kansas City in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY By KATHERINE ANNE SHORTT B.S, Indiana University, Bloomington, 2011 M.S, University of Missouri, Kansas City, 2014 Kansas City, Missouri 2018 © 2018 Katherine Shortt All Rights Reserved IDENTIFICATION OF NOVEL REGULATORY GENES IN ACETAMINOPHEN INDUCED HEPATOCYTE TOXICITY BY A GENOME-WIDE CRISPR/CAS9 SCREEN Katherine Anne Shortt, Candidate for the Doctor of Philosophy degree, University of Missouri-Kansas City, 2018 ABSTRACT Acetaminophen (APAP) is a commonly used analgesic responsible for over 56,000 overdose-related emergency room visits annually. A long asymptomatic period and limited treatment options result in a high rate of liver failure, generally resulting in either organ transplant or mortality. The underlying molecular mechanisms of injury are not well understood and effective therapy is limited. Identification of previously unknown genetic risk factors would provide new mechanistic insights and new therapeutic targets for APAP induced hepatocyte toxicity or liver injury. This study used a genome-wide CRISPR/Cas9 screen to evaluate genes that are protective against or cause susceptibility to APAP-induced liver injury. HuH7 human hepatocellular carcinoma cells containing CRISPR/Cas9 gene knockouts were treated with 15mM APAP for 30 minutes to 4 days. A gene expression profile was developed based on the 1) top screening hits, 2) overlap with gene expression data of APAP overdosed human patients, and 3) biological interpretation including assessment of known and suspected iii APAP-associated genes and their therapeutic potential, predicted affected biological pathways, and functionally validated candidate genes.
    [Show full text]
  • Cryo-EM Structures of Calcium Homeostasis Modulator Channels In
    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.31.928093; this version posted January 31, 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. 1 Title: 2 Cryo-EM structures of calcium homeostasis modulator channels 3 in diverse oligomeric assemblies 4 5 One Sentence Summary: 6 Cryo-EM structures reveal the ATP conduction and oligomeric assembly 7 mechanisms of CALHM channels. 8 9 Authors: 10 Kanae Demura1,†, Tsukasa Kusakizako1,†, Wataru Shihoya1,†, Masahiro Hiraizumi1,2,†, 11 Kengo Nomura3, Hiroto Shimada1, Keitaro Yamashita1,4, Tomohiro Nishizawa1, Akiyuki 12 Taruno3, 5,*, Osamu Nureki1,* 13 14 Affiliations: 15 1Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 16 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; 2Discovery Technology Laboratories, 17 Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida, 18 Aoba-ku, Yokohama 227-0033, Japan; 3Department of Molecular Cell Physiology, Kyoto 19 Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan; 20 4RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan; 21 5Japan Science and Technology Agency, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 22 332-0012, Japan. 23 24 * To whom reprint requests should be addressed: [email protected] (A.T.), 25 [email protected] (O.N.). † These authors contributed equally to this work. 26 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.31.928093; this version posted January 31, 2020.
    [Show full text]
  • Genome-Wide Association Studies in the Partial Epilepsies CLÁUDIA José Franco Bacanh
    GENETIC STUDIES OF THE COMMON EPILEPSIES: genome-wide association studies in the partial epilepsies CLÁUDIA José Franco Bacanhim Santos CATARINO UCL Institute of Neurology Queen Square London WC1N 3BG A thesis for submission to University College London for the degree of Doctor of Philosophy 2013. Abstract This thesis discusses four studies, looking for genetic determinants of common epilepsies: 1) A genome-wide association study (GWAS) of partial epilepsies (PE), which was the first published GWAS in the field of epilepsy (Chapter 4). 2) A GWAS of mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) (Chapter 5). 3) A case series of patients with refractory MTLE, operated and found to have large microdeletions at 16p13.11, 15q11.2 and others (Chapter 6). 4) A clinical, genetic and neuropathologic study of a series of patients with Dravet syndrome (DS), diagnosed as adults, including genotype-phenotype correlation analysis (Chapter 7). The main findings include: 1) The GWAS of PE has not yielded any genome-wide significant association with common genetic variants, possibly because of insufficient power and phenotypical heterogeneity. It is, however, a strong foundation for further studies, illustrating the feasibility of large multicentre GWAS in the epilepsies (Chapter 4). 2) The GWAS of MTLEHS yielded a borderline genome-wide statistically significant association with three common genetic variants close or intronic to the SCN1A gene, especially in MTLEHS with antecedents of childhood febrile seizures (Chapter 5). 3) Large microdeletions at 16p13.11 and others were found in patients with MTLEHS and not only in idiopathic non-lesional epilepsies. Good outcome after resective epilepsy surgery is possible in “typical” MTLEHS even with large microdeletions (Chapter 6).
    [Show full text]
  • Generation of Calhm1 Knockout Mouse and Characterization of Calhm1 Gene Expression
    Protein Cell 2012, 3(6): 470–480 DOI 10.1007/s13238-012-2932-6 Protein & Cell RESEARCH ARTICLE Generation of Calhm1 knockout mouse and characterization of calhm1 gene expression Junbing Wu1,2, Shengyi Peng1,2, Rong Wu1,2, Yumin Hao1,2, Guangju Ji1, Zengqiang Yuan1 1 State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 2 College of Life Sciences, Graduate School of Chinese Academy of Sciences, Beijing 100049, China Correspondence: [email protected] Received April 8, 2012 Accepted April 24, 2012 ABSTRACT mentia in elderly people worldwide. Advanced aging, family history and heredity are major risk factors of AD. Although the Alzheimer’s disease (AD) is the most common neurode- etiology of AD is far more complicated, two pathological generative disease among elderly people worldwide. hallmarks are common, namely extracellular amyloid plaques Several genes have been validated to be associated with depositing of amyloid β (Aβ) and intracellular neurofibriliary AD, and calcium homeostasis modulator 1 (Calhm1) is tangles (NFT) triggered by hyperphosphorylated tau (Ballard the latest suspected one. To investigate the biological et al., 2011). Genetically, familial mutants of deterministic and pathological function of Calhm1 systematically, we genes, amyloid precursor protein (APP) on chromosome 21, generated a Calhm1 conventional knockout mouse. presenilin 1 (PS1) on chromosome 14 and presenilin 2 (PS2) However, both the male and female of elderly Calhm1 on chromosome 1, directly cause early-onset AD (EOAD) knockout (KO) mice showed similar ability to their wild before age 60, accounting for about 5% of all AD cases type littermates in spatial learning and memory retrieving.
    [Show full text]
  • Genetic Association of Complement Receptor 1 Polymorphism
    Alzheimer’s & Dementia 7 (2011) e124–e129 Genetic association of complement receptor 1 polymorphism rs3818361 in Alzheimer’s disease Carmen Antunez a,b, Merce Boadac,d, Jesus Lopez-Arrieta e, Concha Moreno-Reyf, Isabel Hernandezc, Juan Marına, Javier Gayanf, Alzheimer’s Disease Neuroimaging Initiative, Antonio Gonzalez-Perezf, Luis M. Realf, Montserrat Alegretc, Lluis Tarragac, Reposo Ramırez-Lorcaf, Agustın Ruizf,* aDementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain bAlzheimUr Foundation, Murcia, Spain cMemory Clinic of Fundacio ACE, Institut Catala de Neurciencies Aplicades, Barcelona, Spain dInstitut de Recerca, Universitat Autonoma de Barcelona (VHIR-UAB), Hospital Universitari Vall d’Hebron, Barcelona, Spain eMemory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain fDepartment of Structural Genomics, Neocodex, Sevilla, Spain Abstract Complement receptor 1 gene polymorphism rs3818361 was recently shown to increase the risk of Alzheimer’s disease (AD). We performed an independent replication study of this genetic variant in 2470 individuals from Spain. By applying an allelic model, we observed a trend toward an association between this marker and late-onset AD susceptibility in our case–control study (odds ratio 5 1.114, 95% confidence interval: 0.958–1.296, P 5.16). Meta-analysis of available studies (n 5 31,771 individuals), including previous studies and public genome-wide association study resources (Alzheimer’s Disease Neuroimaging Initiative, Translational Genomics Research Institute, and Multi-site Collaborative Study for Genotype-Phenotype Associations in Alzheimer’s Disease), strongly supports the effect of rs3818361 (odds ratio 5 1.180, 95% confidence interval: 1.113–1.252, P , 2.99E-8) and suggests the existence of between-study heterogeneity (P , .05).
    [Show full text]
  • GENOME-WIDE ANALYSES of GENES AFFECTING GROWTH, MUSCLE ACCRETION and FILLET QUALITY TRAITS in RAINBOW TROUT by Ali Reda Eid
    GENOME-WIDE ANALYSES OF GENES AFFECTING GROWTH, MUSCLE ACCRETION AND FILLET QUALITY TRAITS IN RAINBOW TROUT by Ali Reda Eid Ali A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Molecular Biosciences Middle Tennessee State University August 2019 Dissertation committee: Dr. Mohamed (Moh) Salem, Chair Dr. Anthony L. Farone Dr. Jason Jessen Dr. Mary Farone Dr. Elliot Altman I dedicate this research to my parents, my wife and kids for their unwavering love and endless support throughout this long trip. Without their great selflessness, sacrifices, and prayers, I would not have been able to fulfill and achieve this dream of mine ii ACKNOWLEDGMENTS First of all, I would like to express my deepest respect and indebtedness to my PhD dissertation advisor Dr. Mohamed Salem for his continuous guidance, endless support and encouragement throughout my PhD research work. I was fortunate to have him as my primary advisor who gave me this opportunity to grow as a professional research scholar. He was never wavering in his support, and was always patient and supportive during the more grueling portions of this investigation. My deepest appreciation and respect also go to my PhD dissertation committee members Dr. Anthony Farone, Dr. Elliot Altman, Dr. Jason Jessen, and Dr. Mary Farone for guiding me with their expertise to accomplish this project. I would like to thank Dr. Rafet Al-Tobasei for working together in several projects and sharing scientific ideas. I also want to acknowledge my collaborators Dr. Yniv Palti, and Dr. Timothy D. Leeds from National Center for Cool and Cold Water Aquaculture (NCCCWA)/USDA.
    [Show full text]
  • CALHM1 Deficiency Impairs Cerebral Neuron Activity and Memory Flexibility in Mice Received: 28 July 2015 Valérie Vingtdeux1,*,†,‡,§, Eric H
    www.nature.com/scientificreports OPEN CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice Received: 28 July 2015 Valérie Vingtdeux1,*,†,‡,§, Eric H. Chang2,*, Stephen A. Frattini2, Haitian Zhao1, Accepted: 18 March 2016 Pallavi Chandakkar1, Leslie Adrien1, Joshua J. Strohl2, Elizabeth L. Gibson2, Makoto Ohmoto3, Published: 12 April 2016 Ichiro Matsumoto3, Patricio T. Huerta2,4 & Philippe Marambaud1 CALHM1 is a cell surface calcium channel expressed in cerebral neurons. CALHM1 function in the brain remains unknown, but recent results showed that neuronal CALHM1 controls intracellular calcium signaling and cell excitability, two mechanisms required for synaptic function. Here, we describe the generation of Calhm1 knockout (Calhm1−/−) mice and investigate CALHM1 role in neuronal and cognitive functions. Structural analysis revealed that Calhm1−/− brains had normal regional and cellular architecture, and showed no evidence of neuronal or synaptic loss, indicating that CALHM1 deficiency does not affect brain development or brain integrity in adulthood. However,Calhm1 −/− mice showed a severe impairment in memory flexibility, assessed in the Morris water maze, and a significant disruption of long-term potentiation without alteration of long-term depression, measured in ex vivo hippocampal slices. Importantly, in primary neurons and hippocampal slices, CALHM1 activation facilitated the phosphorylation of NMDA and AMPA receptors by protein kinase A. Furthermore, neuronal CALHM1 activation potentiated the effect of glutamate on the expression of c-Fos and C/EBPβ, two immediate- early gene markers of neuronal activity. Thus, CALHM1 controls synaptic activity in cerebral neurons and is required for the flexible processing of memory in mice. These results shed light on CALHM1 physiology in the mammalian brain.
    [Show full text]
  • Structure and Assembly of Calcium Homeostasis Modulator Proteins Authors: Johanna L Syrjanen1, Kevin Michalski1, Tsung-Han Chou1, Timothy Grant2, Shanlin
    bioRxiv preprint doi: https://doi.org/10.1101/857698; this version posted November 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Title: Structure and assembly of calcium homeostasis modulator proteins Authors: Johanna L Syrjanen1, Kevin Michalski1, Tsung-Han Chou1, Timothy Grant2, Shanlin Rao4,5, Noriko Simorowski1, Stephen J. Tucker4, Nikolaus Grigorieff2,3, and Hiro Furukawa1* Affiliations: 1WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. 2Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA 3RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA. 4Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, United Kingdom. 5Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, United Kingdom. *Correspondence to: [email protected] (H.F.) bioRxiv preprint doi: https://doi.org/10.1101/857698; this version posted November 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Abstract: Biological membranes of many tissues and organs contain large-pore channels designed to permeate a wide variety of ions and metabolites. Examples include connexin, innexin, and pannexin, which form gap junctions and/or bona fide cell surface channels. The most recently identified large-pore channels are the calcium homeostasis modulators (CALHMs), which permeate ions and ATP in a voltage-dependent manner to control neuronal excitability, taste signaling, and pathologies of depression and Alzheimer’s disease.
    [Show full text]