COREB: INTRAVITAL MICROSCOPY AND ANIMAL CORE Projects #1 and #2 are heavily dependent upon the use of laboratory animals for the evaluation of the antithrombotic properties of PDI inhibitors. Mice will be employed for both direct visualization and analysis of thrombus formation using intravital microscopy and for studying the survival of mouse progeny carrying otherwise lethal genetic properties predisposing to thrombosis and fetal/perinatal death. This core will provide services that include the timely availability of specific mice and mouse strains and the maintenance of mouse colonies. An animal technician will maintain the breeding stock and coordinate the timely delivery of mice to the intravital microscopy facility. This person also performs and analyzes via PCR the genotypes of all mice, and maintains a detailed log for the birth (or acquisition), genotyping and utilization of each mouse. As many as 4-6 mice of a specific genotype are used per day for intravital analysis of thrombus formation. Given the importance of intravital imaging and analysis to Projects #1 and #2, a central core facility will be maintained to support these projects. Core B will be administered by Dr. Barbara Furie and co-directed by Glenn Merrill-Skoloff. Mr. Merrill-Skoloff has been associated with the Furie laboratory for 17 years and is the Director of the Intravital Microscopy Facility within the Division of Hemostasis and Thrombosis. An expert at mouse surgery and animal model development, co-developer of the high speed digital multichannel intravital microscopy facility and skilled computer specialist, he has been critical to the success of this work over the past ten years. He is arguably the most sophisticated intravital microscopist working in this field today, and an important resource for this Center grant. He has also trained teams from other institutions who have visited in order to establish similar microscopy facilities elsewhere. In general, intravital thrombosis experiments in mice require about four hours. Three sessions per day are available during the regular workweek, and sessions are also available on Saturday and Sunday for especially long or intensive experiments. Access to the Intravital Microscopy facility is not an issue. Although our funded PPG also uses this facility, we retain sufficient capacity for this Center grant so that no projects will have any delays in gaining access. Since analysis time of data requires about a full day per experimental session, there is ample microscope time for each project member.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHL1-CSR-C (F1))
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Beth Israel Deaconess Medical Center
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Sharda, Anish; Furie, Bruce (2018) Regulatory role of thiol isomerases in thrombus formation. Expert Rev Hematol 11:437-448
Stopa, Jack D; Zwicker, Jeffrey I (2018) The intersection of protein disulfide isomerase and cancer associated thrombosis. Thromb Res 164 Suppl 1:S130-S135
Flaumenhaft, Robert (2017) Advances in vascular thiol isomerase function. Curr Opin Hematol 24:439-445
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Bowley, Sheryl R; Fang, Chao; Merrill-Skoloff, Glenn et al. (2017) Protein disulfide isomerase secretion following vascular injury initiates a regulatory pathway for thrombus formation. Nat Commun 8:14151
Stopa, Jack D; Neuberg, Donna; Puligandla, Maneka et al. (2017) Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight 2:e89373
Flaumenhaft, R (2016) Probing for thiol isomerase activity in thrombi. J Thromb Haemost 14:1067-9
Galinski, Christine N; Zwicker, Jeffrey I; Kennedy, Daniel R (2016) Revisiting the mechanistic basis of the French Paradox: Red wine inhibits the activity of protein disulfide isomerase in vitro. Thromb Res 137:169-73
Schulman, Sol; Bendapudi, Pavan; Sharda, Anish et al. (2016) Extracellular Thiol Isomerases and Their Role in Thrombus Formation. Antioxid Redox Signal 24:1-15
Flaumenhaft, Robert; Furie, Bruce (2016) Vascular thiol isomerases. Blood 128:893-901

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