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CHS Research Grants for 2016

Role of Gfi1b in the formation of platelets and in inherited bleeding disorders

Dr. Tarik Möröy
Institut de recherches cliniques de Montréal (IRCM)
Department of Hematopoiesis and Cancer
Second year funding

Platelets are essential for blood clotting and are formed in the bone marrow by large cells, so-called 'megakaryocytes', which form long protrusions that penetrate into blood vessels, where the shear forces of the blood stream detach small pieces, which form the platelets. Low platelet numbers can be caused by different diseases or can be the result of an inherited disorder that leaves megakaryocytes unable to produce platelets. These heritable diseases are of clinical importance since low platelet numbers can cause excessive bleeding, which can create severe complications for instance during surgery. A better
understanding which factors regulate platelet production is therefore needed to develop new treatments for platelet deficiencies. Recently, mutations in a gene called 'Gfi1b' have been identified in patients with a bleeding disorder caused by low platelet numbers. We have generated mice deficient for this gene and have observed that they show most of the typical symptoms of the human disease associated with the mutated Gfi1b, suggesting that the Gfi1b gene is a critical element in platelet formation. We propose therefore to investigate how this gene functions and regulates platelet formation to gain new insight on how to treat patients with bleeding disorders and platelet deficiencies.

The role of FVIII glycans on the immunogenic potential of FVIII concentrates

Dr. David Lillicrap

Queen’s University – Kingston, Ontario
First year funding

The aim of the studies described in this research proposal are to investigate possible causes for the increased risk of factor VIII inhibitor development that has been documented with one particular form of recombinant factor VIII concentrate. The theory being tested in these experiments is that the recombinant factor VIII in question is “decorated” with a different pattern of sugar molecules that trigger a response from the early, innate arm of the immune defense system. The studies that ate proposed will first determine the pattern of sugars associated with the surface of different forms of recombinant factor VIII. We will then examine the effect of the various recombinant concentrates on the immune cells that cleat factor VIII from blood and provide the initial response to the protein. These experiments will
test whether the immune cells are excessively “activated” by any of the factor VIII concentrates. We will also be able change the sugar content of the factor VIII proteins through chemical means, to see whether this alters the effect on the immune cells. Finally, we will test the potential of the different factor VIII products to produce inhibitors in a novel “humanized” mouse model of hemophilia.

Implementing the assessment of hemophilic arthropathy joint changes over time: quantitative versus semiquantitative MR imaging of cartilage

Lab work studentship

Michelle Quaye
University of Western Ontario – London, Ontario
Under the supervision of Dr. Andrea Doria, Hospital for Sick Children – Toronto, Ontario

Background: Joint disease affects 90% of hemophiliacs greatly contributing to the cost and morbidity of the disease. Cartilage degeneration is the final unfavourable outcome of non-treated hemophilic patients which can be avoided or minimized with the use of prophylaxis. Recent advances in hemophilia prophylaxis have raised the need for accurate noninvasive methods for assessment of early cartilage damage in maturing joints to guide initiation of prophylaxis. Such methods can either be quantitative or semiquantitative.

Objective: The study purpose is to compare a quantitative methodology through manual segmentation of articular cartilage parts (proposed new method) with a semiquantitative score (a priori determined International Prophylaxis Study Group MRI scoring system) and clinical-radiographic methods for short-term (1 year) evaluation of cartilage status in growing ankles of hemophilic children and adolescents. Data from a control group of healthy boys with ages similar to those of participating hemophilic patients will be available for comparison.

Methods: We will segmentate the cartilage on MRIs of 15 hemophilic ankles at two timepoints (baseline, 1 year), and on MRIs of 7 control ankles at a single timepoint using the new quantitative method. The findings of these MRIs will be interpreted by two experienced radiologists using the IPSG score using the conventional semiquantitative method. We will assess associations between interval cartilage changes by the quantitative and semiqualitative methods, and clinical and radiographic scores.

Relevance: The methodology that will be used in this study has the potential to improve the accuracy of interpretation of cartilage findings in maturing joints with hemophilic arthropathy. The results of this research can be used to improve the monitoring of failure to therapy/prophylaxis both in clinical practice and in research in the future. Failure to therapy/prophylaxis could be detected earlier with the proposed new quantitative methodology than with currently used semiquantitative MRI methodology.