Core B (the Microfluidics Core) will design and build microfluidic devices and flow control systems, develop advanced substrate-coating techniques, and work with the laboratories participating in the Program to apply them to studies of surface adhesion of platelet and leukocytes. Core B will set up, upgrade, conjugate with microscopy, and maintain microfluidic systems in the laboratories of the Program, will train the personnel of the laboratories and take part in pilot experiments with the systems. Core B will fabricate microfluidic devices, supply them to the Program laboratories, and modify the devices and techniques based on the feedback from the laboratories. For experiments on substrate adhesion and aggregation of platelets (Projects 1 - 3), Core B will build microfluidic devices subjecting blood to two to three orders-of-magnitude ranges of shear stress in each assay, with shear stress reaching >1000 dynes/cm'^2 for experiments with von Willebrand factor, VWF, (Project 3) and with small amounts of blood (<100 uL for Projects 1 and 2 and <400 uL for Project 3) required for an assay. Platelet adhesion from two different blood samples to identical substrates will be tested in parallel. Substrate coating techniques will be developed to control the site densities of adhesion molecules (collagen, fibrinogen, and VWF) and to test the adhesion to substrates with a range of site densities in a single assay. Micro-channels with constrictions will be fabricated to study the effect of extensional vs. shear flow on the activity of VWF and on VWF-mediated adhesion and aggregation of platelets (Project 3). For experiments on rolling and arrest of leukocytes (Projects 1), Core B will build microfluidic devices with a range of shear stresses and customized substrate coatings. Mixed substrate coatings will be created with site densities of different adhesion molecules (e.g., P-selectin and VCAM-1) independently varied and controlled. Substrates with sharp boundaries between differently coated areas will be produced to test for possible integrin activation by adhesion molecules and to study the dynamics of neutrophil arrest (Project 1). Micro-patterned substrates with ~1um-wide differently coated strips will be made to emulate non-uniform distributions of adhesion molecules expressed on endothelium.

Public Health Relevance

Adhesion of platelets and leukocyte to endothelium and extracellular matrix from flowing blood plays a crucial role in vascular injury and in the initiation of thrombosis. Microfluidics Core Unit B will provide Projects 1 - 3 with the capability to analyze the adhesion in broad ranges of shear stress in microfluidic perfusion chambers using small blood samples. The perfusion chambers will be coated with adhesion molecules, emulating their site densities and snatial distribution.s in vivo

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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Klann, Jane E; Kim, Stephanie H; Remedios, Kelly A et al. (2018) Integrin Activation Controls Regulatory T Cell-Mediated Peripheral Tolerance. J Immunol 200:4012-4023
Weijts, Bart; Gutierrez, Edgar; Saikin, Semion K et al. (2018) Blood flow-induced Notch activation and endothelial migration enable vascular remodeling in zebrafish embryos. Nat Commun 9:5314
Sun, Hao; Lagarrigue, Frederic; Gingras, Alexandre R et al. (2018) Transmission of integrin ?7 transmembrane domain topology enables gut lymphoid tissue development. J Cell Biol 217:1453-1465
Marki, Alex; Buscher, Konrad; Mikulski, Zbigniew et al. (2018) Rolling neutrophils form tethers and slings under physiologic conditions in vivo. J Leukoc Biol 103:67-70
Moccetti, Federico; Brown, Eran; Xie, Aris et al. (2018) Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries. J Am Coll Cardiol 72:1015-1026
Lagarrigue, Frederic; Gingras, Alexandre R; Paul, David S et al. (2018) Rap1 binding to the talin 1 F0 domain makes a minimal contribution to murine platelet GPIIb-IIIa activation. Blood Adv 2:2358-2368
Wolf, Dennis; Anto-Michel, Nathaly; Blankenbach, Hermann et al. (2018) A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense. Nat Commun 9:525
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
Rothmeier, Andrea S; Marchese, Patrizia; Langer, Florian et al. (2017) Tissue Factor Prothrombotic Activity Is Regulated by Integrin-arf6 Trafficking. Arterioscler Thromb Vasc Biol 37:1323-1331

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