DOCSLIB.ORG

Genome‐Wide Analysis of Genetic Determinants Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genome‐Wide Analysis of Genetic Determinants Of Journal of Thrombosis and Haemostasis, 16: 2024–2034 DOI: 10.1111/jth.14258 ORIGINAL ARTICLE Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity M. OLSSON,* T. M. STANNE,* A. PEDERSEN,* E. LORENTZEN,† E. KARA,‡ A. MARTINEZ-PALACIAN,‡ N. P. RØNNOW SAND,§ A. F. JACOBSEN,¶ P. M. SANDSET,** € J. J. SIDELMANN,†† G. ENGSTROM , ‡‡ O. MELANDER,‡‡ S. M. KANSE‡ and C . J E R N * *Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg; †Bioinformatics Core Facility, University of Gothenburg, Gothenburg, Sweden; ‡Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; §Department of Cardiology, Hospital of South West Denmark, Esbjerg and Department of Regional Health Research, Faculty of Health Science, University of Southern Denmark, Esbjerg, Denmark; ¶Department of Obstetrics, Oslo University Hospital and University of Oslo; **Department of Hematology, Oslo University Hospital and University of Oslo, Oslo, Norway; ††Unit for Thrombosis Research, Department of Regional Health Research, Faculty of Health Science, University of Southern Denmark, Esbjerg, Denmark; and ‡‡Department of Clinical Sciences, Malmo,€ Lund University, Lund, Sweden To cite this article: Olsson M, Stanne TM, Pedersen A, Lorentzen E, Kara E, Martinez-Palacian A, Rønnow Sand NP, Jacobsen AF, Sandset PM, Sidelmann JJ, Engstrom€ G, Melander O, Kanse SM, Jern C. Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity. J Thromb Haemost 2018; 16: 2024–34. study (GWAS) on plasma FSAP activity amongst 3230 Essentials Swedish subjects. Directly genotyped rare variants were also analyzed with gene-based tests. Using GWAS, we • Knowledge of genetic regulators of plasma factor VII confirmed the strong association between the Marburg-I activating protease (FSAP) levels is limited. variant and FSAP activity. HABP2 was also significant • We performed a genome-wide analysis of variants influ- in the gene-based analysis, and remained significant encing FSAP activity in Scandinavian cohorts. after exclusion of Marburg-I carriers. This was attribu- • We replicated an association for Marburg-1 and identi- table to a rare HABP2 stop variant (rs41292628). Carri- fied an association for a HABP2 stop variant. ers of this stop variant showed a similar reduction in • We identified a novel locus near ADCY2 as a potential FSAP activity as Marburg-I carriers, and this finding additional regulator of FSAP activity. was replicated. A secondary genome-wide significant locus was identified at a 5p15 locus (rs35510613), and Summary. Background: Factor VII-activating protease this finding requires future replication. This common (FSAP) has roles in both coagulation and fibrinolysis. variant is located upstream of ADCY2, which encodes Recent data indicate its involvement in several other a protein catalyzing the formation of cAMP. Results processes, such as vascular remodeling and inflamma- and Conclusions: This study verified the Marburg-I vari- tion. Plasma FSAP activity is highly variable among ant to be a strong regulator of FSAP activity, and healthy individuals and, apart from the low-frequency identified an HABP2 stop variant with a similar impact missense variant Marburg-I (rs7080536) in the FSAP- on FSAP activity. A novel locus near ADCY2 was encoding gene HABP2, determinants of this variation identified as a potential additional regulator of FSAP are unclear. Objectives: To identify novel genetic vari- activity. ants within and outside of the HABP2 locus that influ- ence circulating FSAP activity. Patients/Methods: We Keywords: blood coagulation factors; epidemiology; performed an exploratory genome-wide association genetic variation; hemostasis; plasma. Correspondence: Maja Olsson, Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Box 445, SE-405 30 Gothenburg, Sweden Introduction Tel.: +46 31 343 4805 Factor VII-activating protease (FSAP) is a plasma ser- E-mail: [email protected] ine protease targeting various substrates. FSAP is Received: 8 February 2018 mainly produced by the liver, and is present in the cir- Manuscript handled by: W. Ruf culation as an inactive proenzyme. Activation is trig- Final decision: P. H. Reitsma, 26 July 2018 gered by histones released from apoptotic or necrotic © 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Genome-wide analysis of circulating FSAP activity 2025 cells [1]. The protein was initially separately shown to Methods be involved in fibrinolysis, as an activator of single- chain pro-urokinase, and as an activator of FVII [2–4]. Study design More recently, FVII was recognized as a poor FSAP substrate [5,6], and tissue factor pathway inhibitor This study included 3230 participants from the Malmo€ (TFPI) was identified as a novel substrate. In line with Diet and Cancer (MDC) study and the Sahlgrenska this, impaired FSAP modulation of TFPI levels was Academy Study on Ischemic Stroke (SAHLSIS). suggested as an explanation for the defective thrombus The MDC study is a population-based prospective study formation observed in mice made deficient for FSAP that has been described in detail elsewhere [37]. In brief, all (FSAPÀ/À) [7]. Other studies have shown that FSAP men and women living in the Malmo€ area in southern Swe- has a role not only in vascular compartments [8–10], den and born in 1923–1950 were invited to participate. The but also in liver fibrosis [11,12], inflammation [13–16], participation rate was 41% [38]. The present study is based and cancer [17,18]. In vivo experiments in wild-type and on the MDC Cardiovascular Cohort, which randomly FSAPÀ/À mice support a role for FSAP in vascular selected participant from the MDC study [39]. We included remodeling, liver fibrosis, neointima formation, and subjects without both prevalent (i.e. at baseline) and inci- arteriogenesis [11,19–21]. dent cardiovascular disease (CVD) with biobanked plasma Epidemiological studies have shown that circulating available for FSAP activity measurements (n = 2030). FSAP activity is increased in women as compared with The SAHLSIS is a case–control study for which FSAP men, and is further enhanced by pregnancy or the use activity has been reported [27]. In brief, 600 patients with of oral contraceptives [22–24]. FSAP activity is also ischemic stroke at ages 18–69 years were consecutively increased in subjects with deep vein thrombosis [25] recruited at stroke units in western Sweden [40]. Controls or with coronary heart disease [26] as compared with (n = 600) were selected from population-based health sur- controls. We have found that traditional vascular risk veys or registers to match the cases with regard to age, sex, factors explain very little of the variation in plasma and geographical region [40]. Only control subjects without FSAP activity, i.e. < 10% in healthy individuals [27]. a history of CVD or signs of ischemic heart disease on elec- We have also reported on increased FSAP activity in trocardiogram were included [41]. ischemic stroke cases as compared with controls [27]. Sample sizes and baseline characteristics for the two Furthermore, a region near the FSAP-encoding gene studies are summarized in Table 1. The studies were hyaluronan-binding protein 2 (HABP2) was recently approved by the ethics committee at the respective univer- identified as being associated with young-onset stroke sities. All participants or their next of kin gave informed [28]. consent. An early study of interindividual plasma levels of FSAP in healthy subjects discovered individuals with FSAP activity measurement markedly reduced FSAP activity that was not related to antigen levels [23]. Low levels of FSAP activity were Venous blood samples were collected in tubes containing found to be associated with the minor allele of the 10% by volume of 0.13 mol LÀ1 sodium citrate. Aliquots so-called Marburg-I (MI) single-nucleotide polymor- of plasma were stored at À 80 °C. For the prospective phism (SNP) (rs7080536), which introduces an amino MDC study, blood samples were drawn during the baseline acid change, Gly534Glu (NP_004123.1), in the FSAP examinations in 1991–1996. For the SAHLSIS, blood sam- protein [29]. The MI-SNP has been associated with sev- pling was performed in 1998–2003; at enrollment for con- eral disease processes, such as carotid stenosis [30], trols, and at 3-month follow-up for cases [27,40]. Plasma stroke [31], and liver fibrosis [12]. Associations between levels of FSAP activity were measured with an immunocap- the MI-SNP and venous thrombosis have also been ture activity test, as previously described [23,27]. These reported [32,33], but inconsistent results do exist measurements were performed in 2010 and 2014 for the [25,34–36]. SAHLSIS and the MDC study, respectively. The interassay To our knowledge, only three studies have searched for and intra-assay coefficients of variation (CVs) for FSAP genetic variants associated with FSAP activity, and these activity were 14.7% and 4.7%, respectively, in the SAHL- studies were restricted to variants within HABP2 SIS, as reported in [27], and the interassay CV was 8.2% in [16,27,29]. We hypothesized that there are additional the MDC study. FSAP activity values followed a normal genetic variants that contribute to the variation in circu- distribution, and were not transformed for analysis. lating FSAP activity. Hence, we set out to test this hypothesis by conducting the first genome-wide associa- Genotyping, imputation, and quality control (QC) tion study (GWAS) of this quantitative trait. We used a genotyping platform that is enriched with exome content, DNA was extracted from whole blood, and genotyping and searched for both common and rare genetic variants was performed with either the HumanOmniExpress Exome associated with FSAP activity.
Load more

Recommended publications
  • Anti-HABP2 Monoclonal Antibody, Clone FQS25662 (DCABH-7346) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Anti-HABP2 monoclonal antibody, clone FQS25662 (DCABH-7346) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Product Overview Rabbit monoclonal to HABP2 Antigen Description Cleaves the alpha-chain at multiple sites and the beta-chain between Lys-53 and Lys-54 but not the gamma-chain of fibrinogen and therefore does not initiate the formation of the fibrin clot and does not cause the fibrinolysis directly. It does not cleave (activate) prothrombin and plasminogen but converts the inactive single chain urinary plasminogen activator (pro-urokinase) to the active two chain form. Activates coagulation factor VII. Immunogen Synthetic peptide (the amino acid sequence is considered to be commercially sensitive) within Human HABP2 aa 350-450. The exact sequence is proprietary.Database link: Q14520 Isotype IgG Source/Host Rabbit Species Reactivity Mouse, Rat, Human Clone FQS25662 Purity Tissue culture supernatant Conjugate Unconjugated Applications WB, IHC-P, ICC/IF Positive Control Human fetal liver, HepG2, MCF-7 and A549 lysate. Rat liver tissue. HepG2 cells. Format Liquid Size 100 μl Buffer Preservative: 0.01% Sodium azide; Constituents: 40% Glycerol, 59% PBS, 0.05% BSA Preservative 0.01% Sodium Azide Storage Store at +4°C short term (1-2 weeks). Upon delivery aliquot. Store at -20°C long term. Avoid freeze / thaw cycle. Ship Shipped at 4°C. 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved
    [Show full text]
  • Nº Ref Uniprot Proteína Péptidos Identificados Por MS/MS 1 P01024
    Document downloaded from http://www.elsevier.es, day 26/09/2021. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Nº Ref Uniprot Proteína Péptidos identificados 1 P01024 CO3_HUMAN Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 por 162MS/MS 2 P02751 FINC_HUMAN Fibronectin OS=Homo sapiens GN=FN1 PE=1 SV=4 131 3 P01023 A2MG_HUMAN Alpha-2-macroglobulin OS=Homo sapiens GN=A2M PE=1 SV=3 128 4 P0C0L4 CO4A_HUMAN Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=1 95 5 P04275 VWF_HUMAN von Willebrand factor OS=Homo sapiens GN=VWF PE=1 SV=4 81 6 P02675 FIBB_HUMAN Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 78 7 P01031 CO5_HUMAN Complement C5 OS=Homo sapiens GN=C5 PE=1 SV=4 66 8 P02768 ALBU_HUMAN Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=2 66 9 P00450 CERU_HUMAN Ceruloplasmin OS=Homo sapiens GN=CP PE=1 SV=1 64 10 P02671 FIBA_HUMAN Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=2 58 11 P08603 CFAH_HUMAN Complement factor H OS=Homo sapiens GN=CFH PE=1 SV=4 56 12 P02787 TRFE_HUMAN Serotransferrin OS=Homo sapiens GN=TF PE=1 SV=3 54 13 P00747 PLMN_HUMAN Plasminogen OS=Homo sapiens GN=PLG PE=1 SV=2 48 14 P02679 FIBG_HUMAN Fibrinogen gamma chain OS=Homo sapiens GN=FGG PE=1 SV=3 47 15 P01871 IGHM_HUMAN Ig mu chain C region OS=Homo sapiens GN=IGHM PE=1 SV=3 41 16 P04003 C4BPA_HUMAN C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA PE=1 SV=2 37 17 Q9Y6R7 FCGBP_HUMAN IgGFc-binding protein OS=Homo sapiens GN=FCGBP PE=1 SV=3 30 18 O43866 CD5L_HUMAN CD5 antigen-like OS=Homo
    [Show full text]
  • Current Knowledge of Germline Genetic Risk Factors for the Development of Non-Medullary Thyroid Cancer
    G C A T T A C G G C A T genes Review Current Knowledge of Germline Genetic Risk Factors for the Development of Non-Medullary Thyroid Cancer Kinga Hi ´ncza 1,* , Artur Kowalik 1 and Aldona Kowalska 2,3 1 Department Molecular Diagnostics, Holycross Centre, 25-734 Kielce, Poland 2 The Faculty of Health Sciences of the Jan Kochanowski University, 25-317 Kielce, Poland 3 Endocrinology Clinic of Holycross Cancer Centre, 25-734 Kielce, Poland * Correspondence: [email protected]; Tel.: +48-4136-742-58 Received: 16 May 2019; Accepted: 25 June 2019; Published: 26 June 2019 Abstract: The thyroid is the most common site of endocrine cancer. One type of thyroid cancer, non-medullary thyroid cancer (NMTC), develops from follicular cells and represents approximately 90% of all thyroid cancers. Approximately 5%–15% of NMTC cases are thought to be of familial origin (FNMTC), which is defined as the occurrence of the disease in three or more first-degree relatives of the patient. It is often divided into two groups: Syndrome-associated and non-syndromic. The associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex and Werner syndrome. The hereditary factors contributing to the unfavorable course of FNMTC remain poorly understood; therefore, considerable effort is being expended to identify contributing loci. Research carried out to date identifies fourteen genes (DICER1, FOXE1, PTCSC2, MYH9, SRGAP1, HABP2, BRCA1, CHEK2, ATM, RASAL1, SRRM2, XRCC1, TITF-1/NKX2.1, PTCSC3) associated with vulnerability to FNMTC that are not related to hereditary syndromes. In this review, we summarize FNMTC studies to date, and provide information on genes involved in the development of non-syndromic familial non-medullary thyroid cancers, and the significance of mutations in these genes as risk factors.
    [Show full text]
  • HABP2 Sirna (Human)
    For research purposes only, not for human use Product Data Sheet HABP2 siRNA (Human) Catalog # Source Reactivity Applications CRH2056 Synthetic H RNAi Description siRNA to inhibit HABP2 expression using RNA interference Specificity HABP2 siRNA (Human) is a target-specific 19-23 nt siRNA oligo duplexes designed to knock down gene expression. Form Lyophilized powder Gene Symbol HABP2 Alternative Names HGFAL; PHBP; Hyaluronan-binding protein 2; Factor VII-activating protease; Factor seven-activating protease; FSAP; Hepatocyte growth factor activator-like protein; Plasma hyaluronan-binding protein Entrez Gene 3026 (Human) SwissProt Q14520 (Human) Purity > 97% Quality Control Oligonucleotide synthesis is monitored base by base through trityl analysis to ensure appropriate coupling efficiency. The oligo is subsequently purified by affinity-solid phase extraction. The annealed RNA duplex is further analyzed by mass spectrometry to verify the exact composition of the duplex. Each lot is compared to the previous lot by mass spectrometry to ensure maximum lot-to-lot consistency. Components We offers pre-designed sets of 3 different target-specific siRNA oligo duplexes of human HABP2 gene. Each vial contains 5 nmol of lyophilized siRNA. The duplexes can be transfected individually or pooled together to achieve knockdown of the target gene, which is most commonly assessed by qPCR or western blot. Our siRNA oligos are also chemically modified (2’-OMe) at no extra charge for increased Application key: E- ELISA, WB- Western blot, IH- Immunohistochemistry,
    [Show full text]
  • The Structure, Function and Evolution of the Extracellular Matrix: a Systems-Level Analysis
    The Structure, Function and Evolution of the Extracellular Matrix: A Systems-Level Analysis by Graham L. Cromar A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Molecular Genetics University of Toronto © Copyright by Graham L. Cromar 2014 ii The Structure, Function and Evolution of the Extracellular Matrix: A Systems-Level Analysis Graham L. Cromar Doctor of Philosophy Department of Molecular Genetics University of Toronto 2014 Abstract The extracellular matrix (ECM) is a three-dimensional meshwork of proteins, proteoglycans and polysaccharides imparting structure and mechanical stability to tissues. ECM dysfunction has been implicated in a number of debilitating conditions including cancer, atherosclerosis, asthma, fibrosis and arthritis. Identifying the components that comprise the ECM and understanding how they are organised within the matrix is key to uncovering its role in health and disease. This study defines a rigorous protocol for the rapid categorization of proteins comprising a biological system. Beginning with over 2000 candidate extracellular proteins, 357 core ECM genes and 524 functionally related (non-ECM) genes are identified. A network of high quality protein-protein interactions constructed from these core genes reveals the ECM is organised into biologically relevant functional modules whose components exhibit a mosaic of expression and conservation patterns. This suggests module innovations were widespread and evolved in parallel to convey tissue specific functionality on otherwise broadly expressed modules. Phylogenetic profiles of ECM proteins highlight components restricted and/or expanded in metazoans, vertebrates and mammals, indicating taxon-specific tissue innovations. Modules enriched for medical subject headings illustrate the potential for systems based analyses to predict new functional and disease associations on the basis of network topology.
    [Show full text]
  • HABP2 Rabbit Polyclonal Antibody – TA335072 | Origene
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TA335072 HABP2 Rabbit Polyclonal Antibody Product data: Product Type: Primary Antibodies Applications: WB Recommended Dilution: WB Reactivity: Human Host: Rabbit Isotype: IgG Clonality: Polyclonal Immunogen: The immunogen for anti-HABP2 antibody: synthetic peptide directed towards the middle region of human HABP2. Synthetic peptide located within the following region: EPSTKLPGFDSCGKTEIAERKIKRIYGGFKSTAGKHPWQASLQSSLPLTI Formulation: Liquid. Purified antibody supplied in 1x PBS buffer with 0.09% (w/v) sodium azide and 2% sucrose. Note that this product is shipped as lyophilized powder to China customers. Purification: Affinity Purified Conjugation: Unconjugated Storage: Store at -20°C as received. Stability: Stable for 12 months from date of receipt. Predicted Protein Size: 63 kDa Gene Name: hyaluronan binding protein 2 Database Link: NP_004123 Entrez Gene 3026 Human Q14520 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 HABP2 Rabbit Polyclonal Antibody – TA335072 Background: HABP2 is an extracellular serine protease that binds hyaluronic acid and is involved in cell adhesion. It is synthesized as a single chain, but then undergoes an autoproteolytic event to form the functional heterodimer. Further autoproteolysis leads to smaller, inactive peptides. This protease is known to cleave urinary plasminogen activator, coagulation factor VII, and the alpha and beta chains of fibrinogen, but not prothrombin, plasminogen, or the gamma chain of fibrinogen.
    [Show full text]
  • Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 13 October 2019 doi:10.20944/preprints201910.0154.v1 Article Whole genome sequencing of familial non-medullary thyroid cancer identifies germline alterations in MAPK/ERK and PI3K/AKT signaling pathways Aayushi Srivastava 1,2,3,4, Abhishek Kumar 1,5,6, Sara Giangiobbe 1, Elena Bonora 7, Kari Hemminki 1, Asta Försti 1,2,3 and Obul Reddy Bandapalli 1,2,3,* 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany; [email protected] (A.S.), [email protected] (A.K.); [email protected] (S.G.); [email protected] (K.H.); [email protected] (A.F.) 2 Hopp Children’s Cancer Center (KiTZ), D-69120, Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), D-69120, Heidelberg, Germany 4 Medical Faculty, Heidelberg University, D-69120, Heidelberg, Germany 5 Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India 6 Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India 7 S.Orsola-Malphigi Hospital, Unit of Medical Genetics,40138, Bologna, Italy ; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-42-1709 Abstract: Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family.
    [Show full text]
  • Peripheral Nerve Single-Cell Analysis Identifies Mesenchymal Ligands That Promote Axonal Growth
    Research Article: New Research Development Peripheral Nerve Single-Cell Analysis Identifies Mesenchymal Ligands that Promote Axonal Growth Jeremy S. Toma,1 Konstantina Karamboulas,1,ª Matthew J. Carr,1,2,ª Adelaida Kolaj,1,3 Scott A. Yuzwa,1 Neemat Mahmud,1,3 Mekayla A. Storer,1 David R. Kaplan,1,2,4 and Freda D. Miller1,2,3,4 https://doi.org/10.1523/ENEURO.0066-20.2020 1Program in Neurosciences and Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada, 2Institute of Medical Sciences University of Toronto, Toronto, Ontario M5G 1A8, Canada, 3Department of Physiology, University of Toronto, Toronto, Ontario M5G 1A8, Canada, and 4Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1A8, Canada Abstract Peripheral nerves provide a supportive growth environment for developing and regenerating axons and are es- sential for maintenance and repair of many non-neural tissues. This capacity has largely been ascribed to paracrine factors secreted by nerve-resident Schwann cells. Here, we used single-cell transcriptional profiling to identify ligands made by different injured rodent nerve cell types and have combined this with cell-surface mass spectrometry to computationally model potential paracrine interactions with peripheral neurons. These analyses show that peripheral nerves make many ligands predicted to act on peripheral and CNS neurons, in- cluding known and previously uncharacterized ligands. While Schwann cells are an important ligand source within injured nerves, more than half of the predicted ligands are made by nerve-resident mesenchymal cells, including the endoneurial cells most closely associated with peripheral axons. At least three of these mesen- chymal ligands, ANGPT1, CCL11, and VEGFC, promote growth when locally applied on sympathetic axons.
    [Show full text]
  • F IDENTIFICATION of AMYOTROPHIC LATERAL
    IDENTIFICATION OF AMYOTROPHIC LATERAL SCLEROSIS DISEASE MECHANISMS BY CEREBROSPINAL FLUID PROTEOMIC PROFILING by Mahlon Angus Collins B.S. in Neuroscience/Psychology, Central Michigan University, 2006 M.S. in Experimental Psychology, Central Michigan University, 2009 Submitted to the Graduate Faculty of the School of Medicine in partial fulfillment of the requirements for the degree of PhD in Neurobiology University of Pittsburgh 2016 f UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Mahlon Angus Collins It was defended on April 14, 2016 and approved by Carey Balaban, PhD, Professor Michael Gold, PhD, Professor Teresa Hastings, PhD, Associate Professor Janice Robertson, PhD, Associate Professor Rebecca Seal, PhD, Assistant Professor Dissertation Advisor: Robert Bowser, PhD, Adjunct Professor ii Copyright © by Mahlon A. Collins 2016 iii IDENTIFICATION OF AMYOTROPHIC LATERAL SCLEROSIS DISEASE MECHANISMS BY CEREBROSPINAL FLUID PROTEOMIC PROFILING Mahlon Angus Collins, PhD University of Pittsburgh, 2016 Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease. Heterogeneity in clinical, genetic, and pathological features of ALS suggest the disease is a spectrum of disorders each resulting in motor neuron degeneration. Molecular profiling of ALS patients is, therefore, a useful means of characterizing and stratifying the ALS population. To this end, mass spectrometric proteomic profiling was performed on cerebrospinal fluid (CSF) from ALS, healthy control (HC), and other
    [Show full text]
  • Genome-Scale Analysis of DNA Methylation in Lung Adenocarcinoma and Integration with Mrna Expression
    Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Research Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression Suhaida A. Selamat,1 Brian S. Chung,1 Luc Girard,2 Wei Zhang,2 Ying Zhang,3 Mihaela Campan,1 Kimberly D. Siegmund,3 Michael N. Koss,4 Jeffrey A. Hagen,5 Wan L. Lam,6 Stephen Lam,6 Adi F. Gazdar,2 and Ite A. Laird-Offringa1,7 1Department of Surgery, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9176, USA; 2The Hamon Center for Therapeutic Oncology Research and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 3Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9176, USA; 4Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9176, USA; 5Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9176, USA; 6BC Cancer Research Center, BC Cancer Agency, Vancouver, BC V521L3, Canada Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verifi- cation on an independent set of tissues.
    [Show full text]
  • HABP2 ELISA Kit (Human) (GWB-KBBIT7) Lot# GC0354
    HABP2 ELISA Kit (Human) (GWB-KBBIT7) Lot# GC0354 Instructions for use For the quantitative measurement of HABP2 in serum, plasma, tissue homogenates, cell lystates, cell culture supernatants and other biological fluids. Variation between lots can occur. Refer to the manual provided with the kit. This product is intended for research use only. HABP2 ELISA Kit (Human) (GWB-KBBIT7) – Lot# GC0354 Table of Contents 1. Background ................................................................................................................................. 2 2. Assay Summary .......................................................................................................................... 3 3. Storage and Stability ................................................................................................................... 3 4. Kit Components ........................................................................................................................... 3 5. Precautions.................................................................................................................................. 4 6. Required Materials Not Supplied ................................................................................................ 4 7. Technical Application Tips .......................................................................................................... 4 8. Reagent Preparation ................................................................................................................... 5 9. Sample
    [Show full text]
  • Reveals of Candidate Active Ingredients in Justicia and Its Anti-Thrombotic Action of Mechanism Based on Network Pharmacology Ap
    www.nature.com/scientificreports OPEN Reveals of candidate active ingredients in Justicia and its anti‑thrombotic action of mechanism based on network pharmacology approach and experimental validation Zongchao Hong1,5, Ting Zhang2,5, Ying Zhang1, Zhoutao Xie1, Yi Lu1, Yunfeng Yao1, Yanfang Yang1,3,4*, Hezhen Wu1,3,4* & Bo Liu1,3* Thrombotic diseases seriously threaten human life. Justicia, as a common Chinese medicine, is usually used for anti‑infammatory treatment, and further studies have found that it has an inhibitory efect on platelet aggregation. Therefore, it can be inferred that Justicia can be used as a therapeutic drug for thrombosis. This work aims to reveal the pharmacological mechanism of the anti‑thrombotic efect of Justicia through network pharmacology combined with wet experimental verifcation. During the analysis, 461 compound targets were predicted from various databases and 881 thrombus‑related targets were collected. Then, herb‑compound‑target network and protein–protein interaction network of disease and prediction targets were constructed and cluster analysis was applied to further explore the connection between the targets. In addition, Gene Ontology (GO) and pathway (KEGG) enrichment were used to further determine the association between target proteins and diseases. Finally, the expression of hub target proteins of the core component and the anti‑thrombotic efect of Justicia’s core compounds were verifed by experiments. In conclusion, the core bioactive components, especially justicidin D, can reduce thrombosis by regulating F2, MMP9, CXCL12, MET, RAC1, PDE5A, and ABCB1. The combination of network pharmacology and the experimental research strategies proposed in this paper provides a comprehensive method for systematically exploring the therapeutic mechanism of multi‑component medicine.
    [Show full text]