To date, all of the known activators of platelets and hemostasis are soluble and cell matrix molecules. The Kahn lab has demonstrated that interactions between podoplanin (PDPN), a transmembrane protein, and CLEC-2 receptors on the surface of platelets prevent blood-lymphatic mixing throughout life. This pathway requires platelet activation by CLEC2. Studies from the Kahn lab reveal the basis for this phenotype to be a novel form of platelet-mediated hemostasis at the lympho-venous junction that is stimulated by CLEC2 interaction with lymphatic endothelial PDPN. The Bergmeier lab has recently collaborated with the Kahn lab to demonstrate that platelet CLEC2 signaling is also required for hemostasis during vascular inflammation in the lung and skin. The proposed studies will address these new biological roles of PDPN-CLEC2 platelet activation, and investigate the mechanism by which CLEC2 signaling in platelets mediates such non-canonical hemostatic responses.
Aim 1 will investigate the role of PDPN-CLEC2 signaling in preventing pulmonary and inflammatory hemorrhage, two very recently identified functions of this platelet activation pathway.
Aim 2 will test whether this pathway participates in platelet responses to vessel wall injury, determine the mechanism by which the pathway prevents hemorrhage during inflammation, and identify the platelet mechanisms that protect the lymphatic network through lympho- venous hemostasis. These studies will define a recently discovered platelet activation pathway that performs hemostatic roles not previously associated with platelet activation that are highly relevant for human disease.
This proposal investigates the role of a new platelet activation pathway. In this pathway cells that express the surface protein PDPN activate the platelet receptor CLEC2. We have found this pathway to be required for types of hemostasis that are not considered typical, platelet driven hemostasis. These include inter-vascular hemostasis required for blood-lymphatic vascular separation and hemostasis during tissue inflammation. We will use mouse genetic approaches to further study this novel type of hemostasis and platelet function in the context of human diseases.
|Lee, R H; Bergmeier, W (2016) Platelet immunoreceptor tyrosine-based activation motif (ITAM) and hemITAM signaling and vascular integrity in inflammation and development. J Thromb Haemost 14:645-54|
|Stefanini, Lucia; Bergmeier, Wolfgang (2016) RAP1-GTPase signaling and platelet function. J Mol Med (Berl) 94:13-9|
|Lozano, MarÃa Luisa; Cook, Aaron; Bastida, JosÃ© MarÃa et al. (2016) Novel mutations in RASGRP2, which encodes CalDAG-GEFI, abrogate Rap1 activation, causing platelet dysfunction. Blood 128:1282-9|
|Boulaftali, Yacine; Owens 3rd, A Phillip; Beale, Ashley et al. (2016) CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice. Arterioscler Thromb Vasc Biol 36:792-9|
|Piatt, Raymond; Paul, David S; Lee, Robert H et al. (2016) Mice Expressing Low Levels of CalDAG-GEFI Exhibit Markedly Impaired Platelet Activation With Minor Impact on Hemostasis. Arterioscler Thromb Vasc Biol 36:1838-46|
|Bergmeier, Wolfgang; Stefanini, Lucia (2015) Platelet signaling--blood's great balancing act. Oncotarget 6:19922-3|
|Stefanini, Lucia; Paul, David S; Robledo, Raymond F et al. (2015) RASA3 is a critical inhibitor of RAP1-dependent platelet activation. J Clin Invest 125:1419-32|
|Hess, Paul R; Rawnsley, David R; Jakus, ZoltÃ¡n et al. (2014) Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life. J Clin Invest 124:273-84|
|Bergmeier, Wolfgang; Boulaftali, Yacine (2014) Adoptive transfer method to study platelet function in mouse models of disease. Thromb Res 133 Suppl 1:S3-5|
|Boulaftali, Yacine; Hess, Paul R; Kahn, Mark L et al. (2014) Platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling and vascular integrity. Circ Res 114:1174-84|