Project 462058

Each drop of blood contains millions of platelets, tiny cells that patrol the bloodstream and trigger clotting when they encounter cuts. Platelets can also be triggered by infections, inflammation and unstable plaques within blood vessels. The results can be blood clots that block vessels and cause heart attacks, strokes and organ damage. Platelets play many other roles in health and disease, including promoting wound healing and immunity, and contributing to the spread and growth of cancers. Platelets carry and release many different proteins, which are contained in packages called alpha granules. While studying an inherited bleeding condition where platelets lack alpha granules, we identified an important protein called NBEAL2. We found that this protein must be present for alpha granules to form in the bone marrow cells that release platelets into the bloodstream. We went on to discover that other proteins interact with NBEAL2, and are also required for alpha granule production. Recently, we found that NBEAL2 also interacts with membrane lipids called phosphoinositides (PIPs). We propose that specific PIPs are critical for normal platelet alpha granule formation. In this project we will determine how NBEAL2 controls platelet granule formation, via these interactions. We will use methods where my lab has gained internationally-recognized expertise. These include high-resolution microscopy to monitor the development of human and mouse platelets. We will also work with world-class experts at SickKids to determine the protein structure of a key region within NBEAL2. This project will advance understanding of platelet biology. It will assist efforts to control the negative impacts of platelets on health, and enhance their positive roles. We will also open up new avenues of research. Since the proteins we are studying influence a wide range of cells in blood and vessels, our findings will be relevant to many aspects of cell biology, health and disease.