Understanding granule disorders of myeloid cells by unravelling the interactome and function of the Nbeal2 protein

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We have three types of blood cells; red cells carry oxygen to our tissues, white cells fight infections and platelets prevent bleeding. Platelets are smart devices that make the blood clot in the right place, by the right amount, to stop bleeding and allow healing of the damaged vessel wall. Neutrophils, a type of white cell, fight infections by forming traps to capture bugs and producing chemicals to kill them. The flipside to their good roles is that both cells can work together to make blood clot too vigorously. This may lead to clots that prevent blood from reaching the heart or brain, causing a heart attack or stroke. It is important to perform research to better understand how the function of these cells is regulated. As a haematology doctor I diagnose and treat patients with blood disorders and I have an idea to gain insight into how these cells work based on the very rare inherited bleeding condition Gray Platelet Syndrome (GPS). Patients with GPS bleed because their platelets do not function well and may also have autoimmune disease because their white cells do not function well either. Researchers in Cambridge have discovered that changes in the DNA code of the gene NBEAL2 cause GPS. Not a lot is known about this gene but we do know that the platelets and neutrophils lack certain types of granules. These granules are like packages containing many proteins, which the cells release to help fulfil their important functions. It is not surprising, therefore, that platelets and neutrophils from patients with GPS fail to arrest bleeding or form traps for bugs. To better understand the function of the Nbeal2 protein researchers disabled the Nbeal2 gene in mice. As well as having problems with the blood system, these mice also have fragile bones and are protected from the spread of cancer showing that the Nbeal2 protein is involved in many important functions. It is reasonable to assume that Nbeal2 does not act alone, but works together with many other proteins to form and retain granules. Results from recent research indicates it works with 64 other proteins. The project I propose is to identify the critical proteins for granule function within this group of 64. To do this, I will use two different but complementary approaches. Firstly, I will investigate how changes in the Nbeal2 protein identified in patients with GPS alters the interaction with its 64 partner proteins. I will use a new technology to introduce changes in the NBEAL2 gene in stem cells. I will then instruct these gene-modified stem cells to become specialised cells that make platelets. I will use these specialised cells and work with researchers in Dundee to determine whether the gene editing has caused changes in the protein interactions. Secondly, I will work with mathematicians to investigate whether any of the 64 genes for the Nbeal2 partner proteins are changed in patients with unexplained platelet disorders. Researchers in Cambridge have worked with doctors in hospitals in the UK and overseas to engage with families diagnosed with rare platelet disorders. It is very likely that these unexplained disorders are caused by a change in their DNA code. To find these changes they have so far deciphered the entire DNA code of 1013 patients. If I succeed in identifying a presumed new disease-causing gene, then I will invite the affected families for further research studies to confirm this observation.My belief is that the knowledge gained from my project will facilitate the discovery of new genes and proteins which are important for the formation and function of granules in blood cells. The research may bring immediate benefits to the care of patients with inherited blood cell disorders because we can readily introduce a DNA test for more rapid diagnosis. I also hope that in the long term the discoveries made by my research will bring improvements to the prevention and treatment of heart attacks and strokes.