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, but not platelet aggregation mediated by integrin activation. Preliminary 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 PDPN- CLEC2 interaction. 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-arterial, 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 determine what effectors of CLEC2 signaling in platelets function during inflammation and in blood-lymphatic vascular separation. These studies will define a recently discovered platelet activation pathway that performs hemostatic roles not previously associated with platelet activation that are highly relevant to human disease.
Principal Investigator: Charles Abrams Project 2 Narrative Mark L. Kahn 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. Wolfgang Bergmeier The scope of the work is to determine (1) how platelet CLEC2 signaling is triggered at sites of inflammation, and (2) which platelet response(s) are important for the ability of platelets to safeguard vascular integrity. Completion of these studies will define key molecular aspects of this novel form of hemostasis.
|Paul, David S; Casari, Caterina; Wu, Congying et al. (2017) Deletion of the Arp2/3 complex in megakaryocytes leads to microthrombocytopenia in mice. Blood Adv 1:1398-1408|
|Tomaiuolo, Maurizio; Brass, Lawrence F; Stalker, Timothy J (2017) Regulation of Platelet Activation and Coagulation and Its Role in Vascular Injury and Arterial Thrombosis. Interv Cardiol Clin 6:1-12|
|Zhao, Liang; Thorsheim, Chelsea L; Suzuki, Aae et al. (2017) Phosphatidylinositol transfer protein-? in platelets is inconsequential for thrombosis yet is utilized for tumor metastasis. Nat Commun 8:1216|
|Lee, Robert H; Bergmeier, Wolfgang (2017) Sugar makes neutrophils RAGE: linking diabetes-associated hyperglycemia to thrombocytosis and platelet reactivity. J Clin Invest 127:2040-2043|
|Shen, Jian; Sampietro, Sara; Wu, Jie et al. (2017) Coordination of platelet agonist signaling during the hemostatic response in vivo. Blood Adv 1:2767-2775|
|Kononova, Olga; Litvinov, Rustem I; Blokhin, Dmitry S et al. (2017) Mechanistic Basis for the Binding of RGD- and AGDV-Peptides to the Platelet Integrin ?IIb?3. Biochemistry 56:1932-1942|
|Welsh, J D; Poventud-Fuentes, I; Sampietro, S et al. (2017) Hierarchical organization of the hemostatic response to penetrating injuries in the mouse macrovasculature. J Thromb Haemost 15:526-537|
|Bennett, Joel S (2016) Shedding New Light on the Platelet Storage Lesion. Arterioscler Thromb Vasc Biol 36:1715-6|
|Zhu, S; Welsh, J D; Brass, L F et al. (2016) Platelet-targeting thiol reduction sensor detects thiol isomerase activity on activated platelets in mouse and human blood under flow. J Thromb Haemost 14:1070-81|
|Zhou, Zinan; Tang, Alan T; Wong, Weng-Yew et al. (2016) Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature 532:122-6|
Showing the most recent 10 out of 42 publications