Full Text Journal Articles by
Author Justin R Hamilton

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Neutrophil Cathepsin G Proteolysis of Protease Activated Receptor 4 Generates a Novel, Functional Tethered Ligand.

Michelle L Stoller, Indranil Basak, Frederik Denorme, Jesse W Rowley, James Alsobrooks, Krishna Parsawar, Marvin T Nieman, Christian Con Yost, Justin R Hamilton, Paul F Bray, Robert A Campbell,

Platelet-neutrophil interactions regulate ischemic vascular injury. Platelets are activated by serine proteases that cleave protease activated receptor (PAR) amino-termini, resulting in an activating tethered ligand. Neutrophils release cathepsin G (CatG) at sites of injury and inflammation, which activates PAR4 but not PAR1, although the molecular mechanism of CatG-induced PAR4 activation ... Read more >>

Blood Adv (Blood advances)
[2021, :]

Cited: 0 times

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Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis.

Maggie L Kalev-Zylinska, Marie-Christine Morel-Kopp, Christopher M Ward, James I Hearn, Justin R Hamilton, Anna Y Bogdanova,

Ionotropic glutamate receptors include <i>α</i>-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), kainate receptors (KAR), and <i>N</i>-methyl-D-aspartate receptors (NMDAR). All function as cation channels; AMPAR and KAR are more permeable to sodium and NMDAR to calcium ions. Compared to the brain, receptor assemblies in platelets are unusual, suggesting distinctive functionalities.There is convincing evidence that ... Read more >>

Platelets (Platelets)
[2021, 32(8):998-1008]

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Determination of PAR4 numbers on the surface of human platelets: no effect of the single nucleotide polymorphism rs773902.

Simeng Li, Volga Tarlac, Roberto B I Christanto, Shauna L French, Justin R Hamilton,

The thrombin receptor, protease-activated receptor 4 (PAR4), is important for platelet activation and is the target of emerging anti-thrombotic drugs. A frequently occurring single nucleotide polymorphism (SNP; rs773902) causes a function-altering PAR4 sequence variant (NC_000019.10:p.Ala120Thr), whereby platelets from Thr120-expressing individuals are hyper-responsive to PAR4 agonists and hypo-responsive to some PAR4 ... Read more >>

Platelets (Platelets)
[2021, 32(7):988-991]

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Disrupting the platelet internal membrane via PI3KC2α inhibition impairs thrombosis independently of canonical platelet activation.

Maria V Selvadurai, Mitchell J Moon, Simon J Mountford, Xiao Ma, Zhaohua Zheng, Ian G Jennings, Natasha M Setiabakti, Rizani P Iman, Rose J Brazilek, Nurul Aisha Z Abidin, Gaëtan Chicanne, Sonia Severin, Alyce J Nicholls, Connie H Y Wong, Jean-Yves Rinckel, Anita Eckly, Christian Gachet, Warwick S Nesbitt, Philip E Thompson, Justin R Hamilton,

Arterial thrombosis causes heart attacks and most strokes and is the most common cause of death in the world. Platelets are the cells that form arterial thrombi, and antiplatelet drugs are the mainstay of heart attack and stroke prevention. Yet, current drugs have limited efficacy, preventing fewer than 25% of ... Read more >>

Sci Transl Med (Science translational medicine)
[2020, 12(553):]

Cited: 1 time

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Analysis of the F2LR3 (PAR4) Single Nucleotide Polymorphism (rs773902) in an Indigenous Australian Population.

Dian Ningtyas, Russell J Thomson, Volga Tarlac, Shivashankar H Nagaraj, Wendy Hoy, John D Mathews, Simon J Foote, Elizabeth E Gardiner, Justin R Hamilton, Brendan J McMorran,

The F2RL3 gene encoding protease activated receptor 4 (PAR4) contains a single nucleotide variant, rs773902, that is functional. The resulting PAR4 variants, Thr120, and Ala120, are known to differently affect platelet reactivity to thrombin. Significant population differences in the frequency of the allele indicate it may be an important determinant ... Read more >>

Front Genet (Frontiers in genetics)
[2020, 11:432]

Cited: 0 times

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Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?

Simeng Li, Volga Tarlac, Justin R Hamilton,

Protease-activated receptors (PARs) are a family of four GPCRs with a variety of cellular functions, yet the only advanced clinical endeavours to target these receptors for therapeutic gain to date relates to the impairment of platelet function for anti-thrombotic therapy. The only approved PAR antagonist is the PAR1 inhibitor, vorapaxar-the ... Read more >>

Int J Mol Sci (International journal of molecular sciences)
[2019, 20(22):]

Cited: 5 times

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Active Micropump-Mixer for Rapid Antiplatelet Drug Screening in Whole Blood.

Crispin Szydzik, Rose J Brazilek, Farzan Akbaridoust, Charitha de Silva, Mitchell Moon, Ivan Marusic, Andrew S H Ooi, Harshal H Nandurkar, Justin R Hamilton, Arnan Mitchell, Warwick S Nesbitt,

There is a need for scalable automated lab-on-chip systems incorporating precise hemodynamic control that can be applied to high-content screening of new more efficacious antiplatelet therapies. This paper reports on the development and characterization of a novel active micropump-mixer microfluidic to address this need. Using a novel reciprocating elastomeric micropump ... Read more >>

Anal Chem (Analytical chemistry)
[2019, 91(16):10830-10839]

Cited: 2 times

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Illustrated State-of-the-Art Capsules of the ISTH 2019 Congress in Melbourne, Australia.

Christopher M Ward, Robert K Andrews, ,

The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6-10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, ... Read more >>

Res Pract Thromb Haemost (Research and practice in thrombosis and haemostasis)
[2019, 3(3):431-497]

Cited: 3 times

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Shared roles for Scl and Lyl1 in murine platelet production and function.

Sung K Chiu, Stephanie L Orive, Mitchell J Moon, Jesslyn Saw, Sarah Ellis, Benjamin T Kile, Yizhou Huang, Diego Chacon, John E Pimanda, Dominik Beck, Justin R Hamilton, Cedric S Tremblay, David J Curtis,

The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of <i>Scl</i> have not been observed as a cause of inherited thrombocytopenia. We postulated that functional ... Read more >>

Blood (Blood)
[2019, 134(10):826-835]

Cited: 2 times

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The mode of anesthesia influences outcome in mouse models of arterial thrombosis.

Maithili Sashindranath, Sharelle A Sturgeon, Shauna French, Daphne D D Craenmehr, Carly Selan, Susanna Freddi, Chad Johnson, Stephen H Cody, Warwick S Nesbitt, Justin R Hamilton, Harshal H Nandurkar,

<h4>Background</h4>Arterial thrombosis models are important for preclinical evaluation of antithrombotics but how anesthetic protocol can influence experimental results is not studied.<h4>Objectives</h4>We studied how three most commonly used rodent anesthetics affect the induction of thrombosis and thrombus resolution with antiplatelet agent integrilin (Eptifibatide).<h4>Methods</h4>The Folts, electrolytic, and FeCl<sub>3</sub> models of carotid artery ... Read more >>

Res Pract Thromb Haemost (Research and practice in thrombosis and haemostasis)
[2019, 3(2):197-206]

Cited: 4 times

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The PI 3-kinase PI3KC2α regulates mouse platelet membrane structure and function independently of membrane lipid composition.

Maria V Selvadurai, Rose J Brazilek, Mitchell J Moon, Jean-Yves Rinckel, Anita Eckly, Christian Gachet, Peter J Meikle, Harshal H Nandurkar, Warwick S Nesbitt, Justin R Hamilton,

PI3KC2α is a phosphoinositide 3-kinase with a recently reported function in platelets; PI3KC2α-deficient mouse platelets have altered membrane structure and impaired function. Yet, how these membrane changes cause platelet dysfunction remains unknown. Here, focused ion beam-scanning electron microscopy of PI3KC2α-deficient platelet ultrastructure reveals a specific effect on the internal membrane ... Read more >>

FEBS Lett (FEBS letters)
[2019, 593(1):88-96]

Cited: 4 times

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A function-blocking PAR4 antibody is markedly antithrombotic in the face of a hyperreactive PAR4 variant.

Shauna L French, Claudia Thalmann, Paul F Bray, Lynn E Macdonald, Andrew J Murphy, Mark W Sleeman, Justin R Hamilton,

Thrombin activates human platelets via 2 protease-activated receptors (PARs), PAR1 and PAR4, both of which are antithrombotic drug targets: a PAR1 inhibitor is approved for clinical use, and a PAR4 inhibitor is in trial. However, a common sequence variant in human PAR4 (rs773902, encoding Thr120 in place of Ala120) renders ... Read more >>

Blood Adv (Blood advances)
[2018, 2(11):1283-1293]

Cited: 5 times

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Structure and function of the open canalicular system - the platelet's specialized internal membrane network.

Maria V Selvadurai, Justin R Hamilton,

The open canalicular system (OCS) is an internal membrane structure found in platelets. First identified 50 years ago, the OCS comprises a tunneling network of surface-connected channels that appear to play an important role in platelet function. Yet, our understanding of how the OCS forms, how it functions, and what might ... Read more >>

Platelets (Platelets)
[2018, 29(4):319-325]

Cited: 10 times

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Drugs targeting protease-activated receptor-4 improve the anti-thrombotic therapeutic window.

Shauna L French, Justin R Hamilton,

Ann Transl Med (Annals of translational medicine)
[2017, 5(23):464]

Cited: 3 times

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Perinatal lethality of Par4-/- mice delivered by primiparous dams reveals spontaneous bleeding in mice without platelet thrombin receptor function.

Shauna L French, Justin R Hamilton,

Protease-activated receptor 4 (PAR4) is a cell surface G protein-coupled receptor for serine proteases, such as thrombin. Par4<sup>-/-</sup> mice have platelets that are unresponsive to thrombin and thereby allow examination of the importance of thrombin-induced platelet activation in (patho)physiology. Par4<sup>-/-</sup> mice are protected against arterial thrombosis but show no evidence ... Read more >>

Platelets (Platelets)
[2018, 29(2):196-198]

Cited: 2 times

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Inhibition of NMDA receptor function with an anti-GluN1-S2 antibody impairs human platelet function and thrombosis.

Taryn N Green, Justin R Hamilton, Marie-Christine Morel-Kopp, Zhaohua Zheng, Ting-Yu T Chen, James I Hearn, Peng P Sun, Jack U Flanagan, Deborah Young, P Alan Barber, Matthew J During, Christopher M Ward, Maggie L Kalev-Zylinska,

GluN1 is a mandatory component of N-methyl-D-aspartate receptors (NMDARs) best known for their roles in the brain, but with increasing evidence for relevance in peripheral tissues, including platelets. Certain anti-GluN1 antibodies reduce brain infarcts in rodent models of ischaemic stroke. There is also evidence that human anti-GluN1 autoantibodies reduce neuronal ... Read more >>

Platelets (Platelets)
[2017, 28(8):799-811]

Cited: 9 times

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Humanizing the Protease-Activated Receptor (PAR) Expression Profile in Mouse Platelets by Knocking PAR1 into the Par3 Locus Reveals PAR1 Expression Is Not Tolerated in Mouse Platelets.

Shauna L French, Antonia C Paramitha, Mitchell J Moon, Ross A Dickins, Justin R Hamilton,

Anti-platelet drugs are the mainstay of pharmacotherapy for heart attack and stroke prevention, yet improvements are continually sought. Thrombin is the most potent activator of platelets and targeting platelet thrombin receptors (protease-activated receptors; PARs) is an emerging anti-thrombotic approach. Humans express two PARs on their platelets-PAR1 and PAR4. The first ... Read more >>

PLoS One (PloS one)
[2016, 11(10):e0165565]

Cited: 6 times

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Class II Phosphoinositide 3-Kinases as Novel Drug Targets.

Marco Falasca, Justin R Hamilton, Maria Selvadurai, Krithika Sundaram, Aleksandra Adamska, Philip E Thompson,

The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases central to regulating a wide range of important intracellular processes. Despite the vast knowledge around class I PI3Ks, the class II PI3Ks have been neglected, seemingly only due to the chronology of their discovery. Here we focus on the cellular ... Read more >>

J Med Chem (Journal of medicinal chemistry)
[2017, 60(1):47-65]

Cited: 10 times

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Challenges and Opportunities in Protease-Activated Receptor Drug Development.

Justin R Hamilton, JoAnn Trejo,

Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the ... Read more >>

Annu Rev Pharmacol Toxicol (Annual review of pharmacology and toxicology)
[2017, 57:349-373]

Cited: 26 times

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Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock.

Salomé L Gazit, Boubacar Mariko, Patrice Thérond, Benoit Decouture, Yuquan Xiong, Ludovic Couty, Philippe Bonnin, Véronique Baudrie, Sylvain M Le Gall, Blandine Dizier, Nesrine Zoghdani, Jessica Ransinan, Justin R Hamilton, Pascale Gaussem, Pierre-Louis Tharaux, Jerold Chun, Shaun R Coughlin, Christilla Bachelot-Loza, Timothy Hla, Benoit Ho-Tin-Noé, Eric Camerer,

<h4>Rationale</h4>Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The relative importance of S1P sources sustaining these processes remains unclear.<h4>Objective</h4>To address the level of redundancy in bioactive S1P provision to the developing and mature vasculature.<h4>Methods and results</h4>S1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, or ... Read more >>

Circ Res (Circulation research)
[2016, 119(8):e110-26]

Cited: 29 times

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Discovery and antiplatelet activity of a selective PI3Kβ inhibitor (MIPS-9922).

Zhaohua Zheng, Jo-Anne Pinson, Simon J Mountford, Stephanie Orive, Simone M Schoenwaelder, David Shackleford, Andrew Powell, Erin M Nelson, Justin R Hamilton, Shaun P Jackson, Ian G Jennings, Philip E Thompson,

A series of amino-substituted triazines were developed and examined for PI3Kβ inhibition and anti-platelet function. Structural adaptations of a morpholine ring of the prototype pan-PI3K inhibitor ZSTK474 yielded PI3Kβ selective compounds, where the selectivity largely derives from an interaction with the non-conserved Asp862 residue, as shown by site directed mutagenesis. ... Read more >>

Eur J Med Chem (European journal of medicinal chemistry)
[2016, 122:339-351]

Cited: 8 times

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Combined deficiency of PI3KC2α and PI3KC2β reveals a nonredundant role for PI3KC2α in regulating mouse platelet structure and thrombus stability.

Claire Petitjean, Natasha M Setiabakti, Jessica K Mountford, Jane F Arthur, Sarah Ellis, Justin R Hamilton,

The physiological functions and cellular signaling of Class II phosphoinositide 3-kinases (PI3Ks) remain largely unknown. Platelets express two Class II PI3Ks: PI3KC2α and PI3KC2β. PI3KC2α deficiency was recently reported to cause disruption of the internal membrane reserve structure of platelets (open canalicular system, OCS) that results in dysregulated platelet adhesion ... Read more >>

Platelets (Platelets)
[2016, 27(5):402-409]

Cited: 4 times

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Protease-activated receptor 4: from structure to function and back again.

Shauna L French, Justin R Hamilton,

Protease-activated receptors are a family of four GPCRs (PAR1-PAR4) with a number of unique attributes. Nearly two and a half decades after the discovery of the first PAR, an antagonist targeting this receptor has been approved for human use. The first-in-class PAR1 antagonist, vorapaxar, was approved for use in the ... Read more >>

Br J Pharmacol (British journal of pharmacology)
[2016, 173(20):2952-2965]

Cited: 19 times

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Thrombin-induced reactive oxygen species generation in platelets: A novel role for protease-activated receptor 4 and GPIbα.

Naadiya Carrim, Jane F Arthur, Justin R Hamilton, Elizabeth E Gardiner, Robert K Andrews, Niamh Moran, Michael C Berndt, Pat Metharom,

<h4>Background</h4>Platelets are essential for maintaining haemostasis and play a key role in the pathogenesis of cardiovascular disease. Upon ligation of platelet receptors through subendothelial matrix proteins, intracellular reactive oxygen species (ROS) are generated, further amplifying the platelet activation response. Thrombin, a potent platelet activator, can signal through GPIbα and protease-activated ... Read more >>

Redox Biol (Redox biology)
[2015, 6:640-647]

Cited: 22 times

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The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function.

Jessica K Mountford, Claire Petitjean, Harun W Kusuma Putra, Jonathan A McCafferty, Natasha M Setiabakti, Hannah Lee, Lotte L Tønnesen, James D McFadyen, Simone M Schoenwaelder, Anita Eckly, Christian Gachet, Sarah Ellis, Anne K Voss, Ross A Dickins, Justin R Hamilton, Shaun P Jackson,

PI3KC2α is a broadly expressed lipid kinase with critical functions during embryonic development but poorly defined roles in adult physiology. Here we utilize multiple mouse genetic models to uncover a role for PI3KC2α in regulating the internal membrane reserve structure of megakaryocytes (demarcation membrane system) and platelets (open canalicular system) ... Read more >>

Nat Commun (Nature communications)
[2015, 6:6535]

Cited: 28 times

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