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Every type of cell has a unique shape that is fundamental to its function. For example, red blood cells exist as biconcave discs so that they can bend easily when passing through very small blood vessels. Patients with the inherited disorder called spherocytosis have red blood cells with an abnormal, spherical shape. These abnormal red blood cells are not flexible like normal red blood cells, resulting in their early destruction. In some patients this continuous destruction of red blood cells leads to severe anemia, requiring transfusions or splenectomy.
We are studying the proteins within red blood cells that determine the appropriate shape of the cell. These are called cytoskeleton proteins (cyto for cell and skeleton for determining shape, like any skeleton). We have focused on a particular family of proteins, the adducins, and we have shown that disruption of the gene encoding beta adducin causes spherocytosis in mice. This was the first evidence that adducins are crucial to the normal shape of red blood cells. Current studies are aimed at understanding how the adducin genes are turned on at the appropriate time during development of red blood cells. These studies may help us understand the signals involved in maintaining a normal level of red blood cells.
Platelets are specialized to use cytoskeleton proteins in their important function of hemostasis. Platelets circulate in the blood stream in an unactivated state, waiting for the signals to form a plug at a site of bleeding. These signals cause platelets to change shape dramatically and become adherent to one another. The shape changes of the platelet depend upon rapid changes in the organization of the cytoskeleton proteins within the platelet. While some of the moleculer mechanisms involved in platelet activation are understood, there is still a great deal to learn about this complex process. As in other aspects of blood coagulation, fine tuning of the system is crucial because too much or too little platelet activation can be lethal.
We have extended studies of the adducin family of cytoskeleton proteins (discovered in red blood cells) to include platelets. These studies are revealing important insights about the function of cytoskeleton proteins in very different cells. Red blood cells and platelets express some of the same adducins, but also express different adducins that provide for the unique structural characteristics of these different cells. My studies are the first to investigate a role for adducin in regulating the shape changes of platelet activation. Further work is needed to define the role of adducin in platelet structure and function.
Megakaryocytes are the precursor cells found in bone marrow that give rise to circulating blood platelets. My lab is studying several genes that are involved in the process of development of megakaryocytes and the production of platelets. One of these genes, MASTL, has been associated with platelet production because a family with low platelet counts has a mutation in this gene. We are trying to understand how this mutation can cause low platelet counts. We are also studying transcription factors and cytoskeletal proteins that were identified as having higher levels in mature megakaryocytes compared to hematopoietic stem cells. It is hoped that studies on these newly identified genes will help us understand the normal process of megakaryocyte development and platelet production.
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