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Studies of platelet signalling and endothelial cell responses using unique synthetic drugs
Örebro universitet, Institutionen för medicinska vetenskaper.ORCID-id: 0000-0002-5025-9454
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Haemostasis is a complex and tightly regulated process which protects us from bleeding. Platelets are essential for maintained haemostasis. Under normal conditions platelets are calmed by antithrombotic substances release by the endothelium. During vascular injury, the platelets will activate and form a haemostatic plug to prevent bleeding. Inflammatory processes like atherosclerosis can disturb the haemostatic balance and lead to severe consequences like myocardial infarction and stroke. Inhibition of platelets and coagulation are common treatments to prevent unwanted blood clot formation. There is a great need for increased knowledge on the mechanisms of thrombosis and characterisation of new substances with possible therapeutic potential. This thesis used unique synthetic drugs to study platelet signalling and endothelial responses. Paper I showed that both sulfated polysaccharides from seaweed and synthetic glycopolymers which mimic their chemical properties caused platelet activation.

Paper II elucidated the molecular mechanism underlying platelet activation by sulfated glycopolymers and polysaccharides. We found that human platelet activation took place via the Platelet endothelial aggregation receptor 1 (PEAR1), while mouse platelet activation was mainly via C-type lectin-like receptor 2. Aggregation was supported by Glycoprotein Ibα in both species.

Paper III showed the effect of synthetic glycopolymers and natural polysaccharides on cultured human endothelial cells. We found that both the glycopolymers and polysaccharides caused a proinflammatory response after 24h.

In Paper IV, the effect of a synthetic purine analogue with a nitrate ester motif was studied. We found that the purine analogue reduced platelet functions by inhibiting Rho-associated protein kinase (ROCK).

This thesis describes unique synthetic drugs that can be used for further studies of the mechanisms underlying the biological processes of thrombosis and inflammation. The synthetic glycopolymers can be used to further elucidate the physiological role of PEAR1, a potential future therapeutic target.

Ort, förlag, år, upplaga, sidor
Örebro: Örebro University , 2019. , s. 64
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 195
Nyckelord [en]
Haemostasis, glycopolymers, purine analogue, PEAR1, GPIbα, CLEC-2, inflammation, ROCK
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
URN: urn:nbn:se:oru:diva-73147ISBN: 978-91-7529-287-8 (tryckt)OAI: oai:DiVA.org:oru-73147DiVA, id: diva2:1296231
Disputation
2019-05-29, Örebro universitet, Campus USÖ, hörsal C3, Södra Grev Rosengatan 32, Örebro, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-03-14 Skapad: 2019-03-14 Senast uppdaterad: 2019-05-06Bibliografiskt granskad
Delarbeten
1. Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
Öppna denna publikation i ny flik eller fönster >>Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
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2017 (Engelska)Ingår i: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, nr 2, artikel-id UNSP 1600257Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The marine sulfated polysaccharide fucoidan displays superior ability to induce platelet aggregation compared to other sulfated polysaccharides. As such, it is an attractive tool for studying molecular and cellular responses in activated platelets. The heterogeneous structure, however, poses a problem in such applications. This study describes the synthesis of sulfated α-l-fucoside-pendant poly(methacryl amides) with homogeneous structures. By using both thiol-mediated chain transfer and reversible addition-fragmentation chain transfer polymerization techniques, glycopolymers with different chain lengths are obtained. These glycopolymers show platelet aggregation response and surface changes similar to those of fucoidan, and cause platelet activation through intracellular signaling as shown by extensive protein tyrosine phosphorylation. As the platelet activating properties of the glycopolymers strongly mimic those of fucoidan, this study concludes these fucoidan-mimetic glycopolymers are unique tools for studying molecular and cellular responses in human blood platelets.

Ort, förlag, år, upplaga, sidor
Weinheim, Germany: Wiley-VCH Verlagsgesellschaft, 2017
Nyckelord
biological applications of polymers; biomimetic; radical polymerization; reversible addition fragmentation chain transfer; structure-property relations
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:oru:diva-52179 (URN)10.1002/mabi.201600257 (DOI)000394592600012 ()27616165 (PubMedID)2-s2.0-84987653303 (Scopus ID)
Anmärkning

Funding Agency:

AFA Insurance, VR Treatments of the Future grant

Tillgänglig från: 2016-09-21 Skapad: 2016-09-14 Senast uppdaterad: 2019-05-06Bibliografiskt granskad
2. Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
Öppna denna publikation i ny flik eller fönster >>Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
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2019 (Engelska)Ingår i: Blood advances, ISSN 2473-9529, Vol. 3, nr 3, s. 275-287Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

Ort, förlag, år, upplaga, sidor
American Society of Hematology, 2019
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Hematologi
Identifikatorer
urn:nbn:se:oru:diva-72478 (URN)10.1182/bloodadvances.2018024950 (DOI)000458442500007 ()30700416 (PubMedID)2-s2.0-85060943358 (Scopus ID)
Forskningsfinansiär
KK-stiftelsen
Anmärkning

Funding Agencies:

BHF  PG/16/53/32242  RG/13/18/30563 

Deutsche Forschungsgemeinschaft  DFG: Eb 177/14-1 

Fonds voor Wetenschappelijk Onderzoek Vlaanderen grant  G0A6514N 

Tillgänglig från: 2019-02-14 Skapad: 2019-02-14 Senast uppdaterad: 2019-06-18Bibliografiskt granskad
3. Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
Öppna denna publikation i ny flik eller fönster >>Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
urn:nbn:se:oru:diva-74033 (URN)
Tillgänglig från: 2019-05-06 Skapad: 2019-05-06 Senast uppdaterad: 2019-05-06Bibliografiskt granskad
4. A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
Öppna denna publikation i ny flik eller fönster >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
Visa övriga...
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
urn:nbn:se:oru:diva-74034 (URN)
Tillgänglig från: 2019-05-06 Skapad: 2019-05-06 Senast uppdaterad: 2019-05-06Bibliografiskt granskad

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