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Ein preklinisk kanning av Fosfodiesterase 8A sum eitt terapeutiskt mál í tarmbrunasjúkum


Amanda Gratton Vang


Aðrir luttakarar:
Maciej Kaminski, Gisela Djurhuus, Gunnrið Jóanesarson


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Stuðul úr Granskingargrunninum:
533.401 kr.

A preclinical study of phosphodiesterase 8A as a therapeutic target for Inflammatory Bowel Disease

The incidence of IBD, an group of autoimmune diseases that attacks the gastrointestinal tract, on the Faroe Islands is more than double what is found throughout the rest of Scandinavia and Europe and therefore, represents a pressing public health need. Recent epidemiological studies with the Faroese Inflammatory Bowel Disease (IBD) cohort demonstrate that the current high rates of IBD on the Faroe Islands reflect an increase in incidence over the past 15-20 years. There is presently no cure for IBD and many approved drugs aim to control symptoms and have significant side effects or low efficacy profiles. Inhibiting an intracellular enzyme Phosphodiesterase (PDE)8A has been shown decrease cell attachment and inflammation; two goals in development of drugs to treat autoimmune diseases. This study aims to determine if PDE8A protein expression differs between types of IBD using immunohistochemistry to visualize PDE8A in sections from colon biopsies. This study will also collaborate on mouse studies that test a potential drug that targets PDE8A in inflammatory cells. Developing novel drugs that can selectively treat the different forms of IBD would improve the quality of life for IBD patients.

Research Objective
The objective of this study was to investigate the protein expression of PDE8A in the mucosa and submucosa of intestinal biopsies and resections from patients with active Ulcerative Colitis (UC). We aimed to determine (1) if intensity of PDE8S staining correlated to UC progression from mild to severe disease and (2) the subcellular localization of PDE8A in leukocytes and blood vessels since recruitment is a critical step in establishing UC and other inflammatory diseases.

Phosphodiesterase (PDE) inhibitors block termination of intracellular cAMP and have anti-inflammatory effects on leukocytes [1]. However, so far no PDE inhibitors have been successful in clinical trials for UC due to dose-limiting side effects [2]. Recently identified PDE8A has been demonstrated to be involved in the control of leukocyte adhesion to endothelial cells in vitro [3]. PDE8A is the highest affinity enzyme of all known PDEs and a small increase in PDE8A expression may be sufficient to make a therapeutic difference [4]. Therefore, PDE8A inhibitors may have an effect at a lower dosage and be a promising therapy where other PDE drugs have failed. No in situ data exists concerning the cell specific localization in humans of PDE8A protein during UC.

Hematoxylin and Eosin stained tissue resections for potential inclusion in this project were identified during the course of routine histological diagnosis of UC following colonoscopy by the pathologist at The National Hospital of The Faroe Islands. Following inclusion, biopsies or resection pairs (macroscopically uninvolved region and UC region) from 27 patients were included in the cohort and graded using a detailed UC grading scale created for research based histology. Immunohistochemistry was performed on 5 μm FFPE tissue sections using an anti-PDE8A antibody. ImageJ software was used to develop a stain intensity segmentation protocol.

Main Result
Robust PDE8A staining was detected in leukocytes and endothelial cells participating in adhesion and in recently recruited perivascular leukocytes. PDE8A was compartmentalized in subcellular microdomains associated the plasma membrane where leukocytes were in close proximity or contact with endothelial cells.

Localizing PDE8A in inflammatory disease is a unique contribution and relevant as in situ data of PDE8A can link published PDE8A in vitro and in vivo data to clinical disease in humans. While PDE8A protein expression did not collelate with disease severity, this study is the first to demonstrate PDE8A compartmentalization in leukocytes and endothelial cells as they participate in adhesion and transmigration in human UC tissue. PDE8A microdomain signalling domains in leukocytes and intestinal endothelial cells are a potential therapeutic target for UC.


Scientific articles, books, thesis etc.
Nicolina Maria Ovadóttir Cand. Scient in Medicinal Biology and Molecular Biology granted from the Department of Science, Systems and Models, University of Roskilde, Denmark on May 11, 2017.05.26
-Thesis Title: Localization of PDE8A in human Ulcerative Colitis and Colorectal Cancer
-Intern supervisor: Professor Jesper Thorvald Troelsen, University of Roskilde, Denmark
-Thesis supervisor: Amanda Vang, Fróðskaparsetur Føroya

Vang AG, Basole C, Dong H, Nguyen RK, Housley W, Guernsey L, Adami AJ, Thrall RS, Clark RB, Epstein PM and Brocke S (2016) Differential Expression and Function of PDE8 and PDE4 in Effector T cells: Implications for PDE8 as a Drug Target in Inflammation. Front. Pharmacol. 7:259. doi: 10.3389/fphar.2016.00259

Chaitali P Basole, Rebecca K. Nguyen , Katie Lamothe , Amanda G. Vang , Robert B. Clark, George S Baillie , Paul M. Epstein, Stefan Brocke. PDE8 controls CD4 T cell motility through the PDE8A-Raf-1 kinase signaling complex (in revision, Cellular Signaling)

European Congress on Pathology, London, UK 2014
Visualizing Phosphodiesterase 8A a novel therapeutic target for autoimmune and inflammatory diseases
Amanda G. Vang2, PhD; Kári R. Nielsen1, MD; Gunnrið Jóanesarson2; Gisela Djurhuus2; Maciej Kaminski2, MD, PhD
1Department of Medicine, 2Department of Diagnostic Medicine, National Hospital of the Faroe Islands, Tórshavn, Faroe Islands

Best Poster Award: Landssjúkrahúsið Research Day 2016
Imaging mRNA at the single cell level in archived human biopsies
Nicolina Maria Ovadóttir1, Kári R. Nielsen2, Gunnrið Jóanesarson3, Gisela Djurhuus3, Maciej Kaminski3, Amanda Vang3
1Department of Science and Environment (DSE), Roskilde University, Roskilde, Denmark
2Department of Medicine, 3Department of Diagnostic Medicine, National Hospital of the Faroe Islands, Tórshavn, Faroe Islands

Best Poster Award: Landssjúkrahúsið Research Day 2017
Therapeutic target PDE8A is located at the site of adhesion between leukocytes and blood vessels during Ulcerative Colitis
Nicolina Maria Ovadóttir1, Katrin Eivindardóttir Danielsen, Kári R. Nielsen2, Gunnrið Jóanesarson3, Gisela Djurhuus3, Ann Østerø3, Maciej Kaminski3, Amanda Vang3,4
1Department of Science and Environment (DSE), Roskilde University, Roskilde, Denmark, 2Department of Medicine, 3Department of Diagnostic Medicine, National Hospital of the Faroe Islands, Tórshavn, Faroe Islands, 4Center for Health Science Research, Fróðskaparsetur Føroya

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