By using platelets and cell and animal models designed in our laboratory, we investigate the role of platelet and endotelial proteins in the pathophysiology of hemostasis, with the ultimate objective of identifying mechanisms and/or molecules as potential therapeutic targets.
Research areas and current objectives:
1. A first line is intended to clarify the molecular genetic basis and pathogenic mechanisms of hemorrhagic syndromes associated with alterations of surface receptors and other platelet molecules. Currently, we focus mainly on studying the mechanisms involved in platelet dysfunction associated with mutations in the fibrinogen receptor (integrin αIIbβ3) in cases of Glanzmann thrombasthenia and thrombasthenia-like syndromes; analyze the molecular defect and its functional impact on diseases with macrothrombocytopenia such as Bernard-Soulier syndrome and MYH9-related disorders; and identify the responsible gene in familial cases of alteration in the number and size of platelets of unknown cause.
2. In a second line of research we plan to reveal the function, hitherto unknown, of some proteins abundantly expressed on platelets and/or endothelium, through phenotypic characterization of genetically modified mouse lines generated in this laboratory. We have studied the platelets of mice with ablation of the ligand of receptor CD40 (CD40L) at different stages of hematopoietic development, concluding that CD40L fixed to the platelet membrane is involved in the control of hemostasis by acting as a platelet coactivator, but endothelial CD40L has no functional relevance in basal conditions. Moreover, after clarifying the functional significance of the expression of podocalicina (Podxl) in platelets, we have recently discovered that this protein plays an essential role in the control of vascular permeability. Mice lacking Podxl in the endothelium develop a generalized vasculitis with premature death due to organ failure. We intend to clarify the molecular mechanism and validate this animal model for the study of the disease in humans.
Horrillo A, Porras G, Ayuso MS, González-Manchón C . Loss of endothelial barrier integrity in mice with conditional ablation of podocalyxin (Podxl) in endothelial cells. Eur J Cell Biol 95:265-276. doi: 10.1016/j.ejcb.2016.04.006
Yang Z, Zimmerman SE, Tsunezumi J, Braitsch C, Trent C, Bryant DM, Cleaver O, González-Manchón C, Marciano DK . Role of CD34 family members in lumen formation in the developing kidney. Developmental Biology. doi: 10.1016/j.ydbio.2016.08.009
Horrillo A, Fontela T, Arias-Salgado EG, Llobat D, Porras G, Ayuso MS, González-Manchón C . Generation of mice with conditional ablation of the Cd40lg gene: new insights on the role of CD40L. Transgenic Res 23(1): 53-66 (doi:10.1007/s11248-013-9743-2)
Sánchez-Guiu I, Antón AI, Padilla J, Velasco F, Lucia JF, Lozano M, Cid A, Sevivas T, Lopez-Fernandez MF, Vicente V, González-Manchón C, Rivera J, Lozano ML . Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study. Orphanet Journal of Rare Diseases 9:213 doi: 10.1186/s13023-014-0213-6
Fernández D, Horrillo A, Alquezar C, González-Manchón C, Parrilla R, Ayuso MS . Control of cell adhesion and migration by Podocalyxin. Implication of Rac1 and Cdc42. Biochem. Biophys. Res. Commun. DOI 10.1016/j.bbrc.2013.01.112
Gutiérrez-Herrero S, Maia V, Gutiérrez-Berzal J, Calzada N, Sanz M, González-Manchón C, Pericacho M, Ortiz-Rivero S, González-Porras JR, Arechederra M, Porras A, Guerrero C . C3G transgenic mouse models with specific expression in platelets reveal a new role for C3G in platelet clotting through its GEF activity. BBA-Molecular Cell Research (DOI: 10.1016/j.bbamcr.2012.05.021)
Alquezar C, Esteras N, Alzualde A, Moreno F, Ayuso MS, López de Munain A, Martín-Requero A . Inactivation of CDK/pRb pathway normalizes survival pattern of lymphoblasts expressing the FTLD-progranulin mutation c.709-1G>A. PLoS One 7(5):e37057
Darío Fernández, Susana Larrucea, Adam Nowakowski, Miguel Pericacho, Roberto Parrilla, Matilde S. Ayuso . Release of podocalyxin into the extracellular space. Role of metalloproteinases. BBA - Molecular Cell Research 2011;1813(8):1504-1510
Pericacho M, Alonso-Martín S, Larrucea S, González-Manchón C, Fernández D, Sánchez I, Ayuso MS, Parrilla R . Diminished Thrombogenic Responses by Deletion of the Podocalyxin Gene in Mouse Megakaryocytes. PLoS One 6(10):e26025
Roberto Parrilla . Letter to the Editor: ´Megakaryocyte gene targeting mediated by restricted expression of recombinase Cre´. Thromb Haemost. 31;106:554-555.
SAF2007-61701 IP: Matilde Sánchez Ayuso, 2007-2012
PIE-201020E018 IP: Matilde Sánchez Ayuso, 2010-2012
Study of the mechanisms involved in platelet dysfunction associated to dominant mutations of [alpha]IIb[beta]3 integrin. Ministerio de Ciencia e Innovación. BFU2010-15237/BMC IP: Consuelo González Manchón 2011-2013
CIBERER, Proyecto Intramural, PIBER 3 (ref 11-734/112.02) 2011