MCT was well represented at this year’s Haematology Association of Ireland meeting in Cork. A number of PhD students and Post-docs from the Irish Centre for Vascular Biology, has their work selected for presentation at this prestigious annual meeting. Moreover, three of these presentations were awarded prizes;
Presidents Prize: Clive Drakeford, PhD student
Best Scientific Oral Presentation: Dr Sean McCluskey, PostDoc
Best Scientific Poster Presentation: Soracha Ward, PhD student
Additionally, two PhD students, Sean Patmore and Aisling Rehill, scored in the top 20% of submitted abstracts and had their work selected for oral presentations at the meeting.
Our group is a drug discovery lab currently working on the development of a novel Fc gamma receptor IIa inhibitors. FcgRIIa is a low affinity receptor for Fc portion of immunoglobulin G (IgG) and is implicated in a variety of conditions that are still mainly untreatable, such as rheumatoid arthritis, lupus, immune thrombocytopenia, sepsis. FcgRIIa is widely expressed by human innate immune cells, and is the only Fc gamma receptor found on human platelets.
Mainly over-stimulation of the FcgRIIa receptor in these conditions that leads to the progression of the disease. For example, in sepsis the platelets get activated via FcgRIIa in response to bacteria present in the blood, which results in thrombocytopenia and disseminated immune coagulopathy. This causes, not only internal haemorrhage but also formation of blood clots that block peripheral blood vessels leading to sepsis-associated limb loss, heart attacks and/or strokes. Using a targeted approach, such as pharmacophore modelling, our group has developed a small molecule compound that effectively blocks FcgRIIa-mediated platelet aggregation in vitro. In agreement with the chosen targeted approach, this compound was shown to bind to the FcgRIIa directly and possesses specificity for the FcgRII subgroup of the Fcg receptors.
Ultimately, this compound has a great potential to be used for treatment of other FcgRIIa-mediated auto-immune conditions, such as rheumatoid arthritis, lupus and an array of immune thrombocytopenia conditions.
Prof Dermot Cox, Dr Tatiana Devine and Padraig Norton
As some of you know, I have joined RCSI as a StAR research lecturer in June. My plan is to establish a lab on ‘MechanoVascular Biology and Microscopy’. What do I mean by this?
The first part ‘MechanoVascular Biology’ sets the scope. I am interested in how cells in the cardiovascular system use mechanical forces to achieve their tasks. As mechanical and chemical cell functions are tightly related, both play important roles in health and disease. Most research has focused on one or the other aspect, but not both. The novel research field of ‘mechanobiology’ takes an integrative approach to better understand how physical forces co-regulate chemical processes on the molecular level. In my previous work at ETH Zurich, I have studied how fibroblasts sense matrix stiffness and respond to it. Here at RCSI, I want to study platelets in the context of thrombosis and, over the years, investigate their interplay with endothelial cells.
The second part ‘Microscopy’ highlights one of the major working horses in my lab. Following the credo ‘seeing is believing’, watching cells can tell you a lot about how they do things. I use microscopy to test hypothesis but also to discover unexpected behaviour. Over the years, I have developed several new microscopy techniques to look at sub-second dynamic processes, directly measure cellular tractions, or determine the nanoscale architecture of multi-protein structures. These are great tools to better understand how the processes starting from platelet activation and ending with the consolidation of the thrombus are regulated in space and time. For this we will use in vitro models, but I am keen to move in the future towards in vivo imaging.
By now, you may have noticed from my scientific viewpoint and my enthusiasm for technology that my background is in physics. I studied physics with a specialization on biophysics at the Technical University Munich. My PhD work at the Max Planck Institute of Biochemistry focused on electrical stimulation of neurons with extracellular electrodes. After a short postdoc at the Ludwig Maximilians University Munich where I studied bi-molecular binding kinetics in living cells, I moved to ETH Zurich in Switzerland. That’s where I have started with mechanobiology and super-resolution fluorescence microscopy, which I know bring over to RCSI.
A long way is lying ahead of me to cross the bridge towards clinical research. I look forward to having many inspiring discussions with you, already thank you for the ones we had so far, and hope that I can make a valuable contribution to the research here at RCSI!
Looking forward to seeing you at MCT Research Talks on 16th October 2017 at 12.00 TR4!
Bayer announced awards of $2 Million in Hemophilia Research and Patient-care Grants to 16 People at The International Society on Thrombosis and Haemostasis 2017, held in Berlin in July.
Congratulations to Dr. Roger Preston, Irish Centre for Vascular Biology[ICVB], (MCT) who was awarded a prestigious Special Project Award (€200,000) from the Bayer Haemophilia Award Programme to develop novel pro-hemostatic agents for the enhanced treatment of patients with haemophilia.
There was a strong representation from MCT at the ISTH Congress including Professor Dermot Kenny, Professor James O’Donnell, Dr. Roger Preston and their respective teams, and Dr. Dermot Cox, President, SSC* 2018. [*SSC:The Scientific and Standardization Committee].
Orla Willis Fox, Phd student with Dr. Roger Preston (ICVB/MCT), was awarded an ISTH Young Investigator Award for submitting one of the highest ranked abstracts. Her abstract title was ‘Inhibition of Activated Protein C Aspartyl Beta-hydroxylation Restricts Anticoagulant Function but Enhances Cytoprotective Signaling Activity’.
Professor James O’Donnell, ICVB/MCT presented an invited state-of-the-art lecture on his landmark studies on VWF and Cerebral Malaria,Dr. Michelle Lavin, ICVB/MCT on LOVIC [The Low Von Willebrand factor Ireland Cohort (LoVIC)] study, Dr. Sonia Agulia, ICVB/MCT on The Role of Sialylation in low VWF levels andSoracha Ward, ICVB/MCT gave a presentation on VWF Clearance.
Additionally, there was significant interest among the attendees in the ISTH SSC 2018 Annual Meeting which will be held in Dublin 2018; Dr. Dermot Cox, President, SSC 2018 anticipates a record attendance of 3,000 delegates for the Dublin meeting. Olwen Foley , (MCT) managed the Irish stand.
Research talks were presented by Sheila Zarros, Tatyana Devine, Afnan Ali and Padraig Norton. Tatyana and Sheila were talking about challenges in thecharacterisation of novel FCγRIIa inhibitors.
Fc receptors are a widely distributed family of receptors that mediate cellular responses to antibodies or immunoglobulins (Ig). The Fc gamma receptor II, FcgRII (also known as CD32) is a low-affinity receptor for Fc portion of immunoglobulin G (IgG) and has two isoforms FcgRIIa and b. Fcg RIIa is widely expressed by human innate immune cells and is the only Fc gamma receptor found on human platelets.
Our group and others have demonstrated the significance of this receptor in the activation of platelets by bacteria, suggesting that it could be an important target in the treatment of sepsis. Its implications in rheumatoid arthritis, cancer pathogenesis, allergic reactions and flu virus-induced thrombocytopenia were also demonstrated.
Our project is focused on characterisation of novel small molecule compounds designed for targeting FcgRIIa receptor’s IgG binding site to inhibit bacteria-induced platelet aggregation in primary human plasma and investigation of their interactions with the FcgRIIa using surface plasmon resonance technology.
Afnan Ali reported on the role of the Fc gamma Receptor IIa (FcγRIIa) in platelet activation. Platelets express the FcγRIIa and this receptor has been identified as a key receptor in bacterial activation of platelets leading to thrombocytopenia and platelet activation. The aim of this study was to identify drugs that could be re-purposed for the treatment of sepsis and immune-mediated thrombocytopenia. We identified 42 drugs predicted to inhibit binding of IgG1 to the FcγRIIa using virtual high throughput screening. This included 20 antibacterial agents, 3 anti-fungals, 3 antiviral agents, 7 antineoplastics and 3 immunosuppressives. A selection of drugs were tested for inhibition of platelet adhesion to IgG, S. aureus-induced platelet aggregation and assessed for platelet activation. This work has identified multiple drugs that have potential to be to be repositioned for thrombocytopenia, sepsis and autoimmune disorders, as well as providing a possible mechanism of action to explain the immunosuppressive effects of some anti-neoplastics and immunosuppressive drugs.
Prof. Eric S. G. Shaqfeh, Qin M. Qi, Departments of Chemical and of Mechanical Engineering, Stanford University
The inhomogeneous center-of-mass distribution of red blood cells and platelets normal to the flow direction in small vessels plays a significant role in hemostasis, drug delivery and microfluidics. Under pressure-driven flow in channels, the migration of deformable red blood cells at steady state is characterised by a concentration peak at the channel center and a cell-free layer or Fahraeus-Lindqvist layer near the vessel wall.
Rigid particles such as platelets, however, “marginate” and thus develop a near-wall excess concentration. This margination controls the time it takes for the initial stages of platelet binding and clotting in response to trauma.
In this talk, we investigate the time-dependent concentration distribution of red blood cells and platelets in pressure-driven flow by developing and solving a Boltzmann model, advection-diffusion equation for both species. From a fluid mechanics point of view, deformability-induced hydrodynamic lift and shear-induced diffusion are essential mechanisms for the cross-flow particle migration and margination. The governing equation for the distribution of red blood cells includes both lift flux away from the wall and shear-induced diffusion due to cell-cell “collisions”. On the other hand, the governing transport equation for platelets includes shear-induced diffusion from cell-platelet “collisions” and platelet-platelet “collisions”. We demonstrate that these predictions are in good agreement with full boundary element simulations of the margination process and we also compare directly to experimental results. We then examine, within this model and our full boundary element simulations, the time evolution and “entrance length” for red blood cell migration and platelet margination. The resulting complete model can serve as a fast and computationally efficient alternative to large-scale simulation with the application, for example, as a real-time computational tool for microfluidic blood assay systems.
Cardiovascular disease (CVD) is the leading cause of death and disability in the world (approx. 1.9 million deaths per year within the EU). Platelet’s play a key role in this process and hence is why antiplatelet therapy such as aspirin is effective in reducing its incidences. Platelet function testing has a role in identifying those that are at high risk of a CVD related event (example a heart attack) and also identifying those patients that do not respond to their medication. There are a number of platelet function tests on the market however these tests suffer from a number of disadvantages such as expense, high sample volume, requirement for trained lab personal and single drug test capability.
My current research under the supervision of Prof. Dermot Kenny (RCSI) and Dr. Niamh Gilmartin (DCU and DIT) is to work alongside our multi-disciplinary team to produce a cost effective, rapid, small sample volume platelet function assay which can detect the effect of multiple antiplatelet drugs in a single patient blood sample. The project is known as the Platelet Monitoring Biochip (PMB). The PMB device consists of 6 micron sized fibrinogen dots, which are micro contact printed to a Zeonor (plastic) surface, a bright-field imaging system and a custom designed platelet analysis software. Blood is added to the device and rocked for 30 minutes to allow platelets to adhere to the fibrinogen dots. The device has 3 channels, a control (no agonist well), an adenosine diphosphate (ADP) well and an Arachidonic acid (AA) well which can be used to detect P2Y12 platelet inhibition and aspirin effect simultaneously. The PMB device provides a fast, easy and low cost way to determine the effectively of antiplatelet therapy against multiple agonists in whole blood. The device is currently in operation in RCSI Beaumont.