In this application we propose to continue efforts aimed at elucidating von Willebrand factor (VWF) structure and function focusing on four aims.
In aim 1 we will test whether structural elements in the VWF A1 domain (VWFA1) can differentially regulate specific adhesive properties. Preliminary data indicate that the interaction of glycoprotein (GP) Iba with VWFA1 immobilized onto a surface, leading to platelet adhesion, may occur through different mechanisms as compared to binding of soluble VWF mediating platelet aggregation. Our goal is to define the distinctive structural elements underlying the initiation and regulation of specific VWF activities and establish their functional relevance in models of vascular injury.
In aim 2 we intend to ascertain whether a-thrombin can act as a physiologic modulator of VWF adhesive properties. We hypothesize that VWFA1 and a-thrombin establish inter-molecular contacts when bound to the same GPIba receptor, and this may influence the stability of the VWFA1-GPIba bond independently of shear stress. We propose to identify the VWFA1 residues that support the interaction with a-thrombin bound to GPIba, thus defining a novel mechanism for the regulation of VWF function during thrombogenesis.
In aim 3 we propose to evaluate whether a specific IgG found in the human population is a modulator of VWF activity. We have identified in human and mouse blood a specific IgG that binds selectively to VWFA1, and obtained preliminary evidence that this IgG may play a role in thrombus formation. Our goal is to characterize the structure of the specific IgG, define the mode of interaction with VWFA1 and obtain definitive in vivo evidence for its physiopathological significance.
In aim 4 we will define the signaling function of collagen-bound VWF leading to platelet activation. We have characterized distinct intracytoplasmic Ca++ signals that follow platelet adhesion to immobilized VWFA1 or collagen under flow conditions, and found that they are enhanced when platelets interact with collagen-bound VWF. We propose to dissect the mechanisms of platelet activation supported by the collagen-VWF complex and the effects of hydrodynamic force on the process. The results of this research will improve our ability to influence disease processes that involve platelets in atherothrombosis.

Public Health Relevance

Experimental and clinical evidence points to a key role of VWF in thrombus formation, orchestrated by interactions with other proteins and modulated through forces generated by flowing blood. Uderstanding these different functions requires addressing structural details as well as verification of concepts in intravidal models. This wll lead to a better diagnosis and treatment for cardio- and cerebro-vascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of California San Diego
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Lopez-Ramirez, Miguel Alejandro; Fonseca, Gregory; Zeineddine, Hussein A et al. (2017) Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations. J Exp Med 214:3331-3346
Ye, Feng; Yang, Chansik; Kim, Jiyoon et al. (2017) Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains. J Biol Chem 292:9858-9864
Baumer, Yvonne; McCurdy, Sara; Alcala, Martin et al. (2017) CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis. Atherosclerosis 256:105-114
Liao, Zhongji; Kasirer-Friede, Ana; Shattil, Sanford J (2017) Optogenetic interrogation of integrin ?V?3 function in endothelial cells. J Cell Sci 130:3532-3541
Klann, Jane E; Remedios, Kelly A; Kim, Stephanie H et al. (2017) Talin Plays a Critical Role in the Maintenance of the Regulatory T Cell Pool. J Immunol 198:4639-4651
Marki, Alex; Gutierrez, Edgar; Mikulski, Zbigniew et al. (2016) Microfluidics-based side view flow chamber reveals tether-to-sling transition in rolling neutrophils. Sci Rep 6:28870
de la Ballina, Laura R; Cano-Crespo, Sara; González-Muñoz, Elena et al. (2016) Amino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability. J Biol Chem 291:9700-11
Abplanalp, Wesley T; Conklin, Daniel J; Cantor, Joseph M et al. (2016) Enhanced Integrin ?4?1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes. Diabetes 65:3505-3515
Lagarrigue, Frederic; Kim, Chungho; Ginsberg, Mark H (2016) The Rap1-RIAM-talin axis of integrin activation and blood cell function. Blood 128:479-87
Fan, Zhichao; Liu, Wei (2016) Keep Eyes on Integrins. J Immunobiol 1:

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