This is a competitive renewal application for years 21-25 of Program Project Grant HL-44612, which provides support for a coordinated, multi-disciplinary investigation of molecular and cellular mechanisms important to the field of transfusion medicine. Our application reflects ongoing, close collaborative ties that have existed amongst the Project Leaders for more than a decade, and who remain committed to interrelated research projects centered around the biology of blood and vascular cells. In PROJECT 1, Peter Newman seeks to examine the cooperative interactions between platelet integrins and members of the ITAM-family of signaling proteins that regulate platelet activation and adhesion, with relevance for thrombosis and hemostasis, as well as platelet storage and transfusion therapy. In PROJECT 2, Hartmut Weiler will examine the influence of elements of the Protein C pathway on hematopoietic stem cell survival and homing, with implications for the growing field of cellular therapies. PROJECT 3. led by Demin Wang, seeks to define the role of specific B lymphocyte populations in the cellular immune response underlying heparin-induced thrombocytopenia - studies that may transform our ability to diagnose and manage this complex bleeding and clotting disorder. PROJECT 4, led by Debra Newman, proposes to examine platelet signal transduction pathways that differentially regulate platelet activation responses to adhesive ligands, with hopes of identifying novel therapeutic targets and strategies for controlling thrombus formation. In PROJECT 5, Robert Montgomery proposes to examine the ability of von Willebrand factor to direct and stabilize factor Vlll in a series of novel large- and small-animal gene therapy protocols. The Administrative Core will oversee and coordinate the day-to-day scientific and fiscal operation of the Program. The Shared Instrumentation Core will continue to provide centralized instrumentation and expertise for DNA sequence analysis, peptide synthesis, image analysis, histology, flow cytometry, BIAcore analysis, and monoclonal antibody production. The Transgenic/Knockout Mouse Core will assist with vector design, transgenic mouse production, multi-trait breeding, and animal husbandry. Taken together, the overall scientific synergy of ideas, reagents and expertise afforded by these multiple collaborations should enable this Program Project in Transfusion Medicine Research to advance our understanding of the biology of blood and vascular cells, and to apply findings made toward treating blood diseases and enhancing the effectiveness of modern- day transfusion therapy.

Public Health Relevance

The field of Transfusion Medicine encompasses a wide range of clinically-important scientific disciplines that, despite their obvious importance to the nation's health, have historically been under-represented in both human and financial resources. Our Program contains interconnected basic and translational research objectives that span the fields of platelet physiology, hematopoietic stem cell therapy, and blood coagulation factor replacement therapy - all disciplines of central importance to human health and disease. (End of Abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Kindzelski, Andrei L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Bloodcenter of Wisconsin, Inc.
United States
Zip Code
Fahs, Scot A; Hille, Matthew T; Shi, Qizhen et al. (2014) A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 123:3706-13
Shi, Qizhen; Kuether, Erin L; Chen, Yingyu et al. (2014) Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells. Blood 123:395-403
Kanaji, S; Fahs, S A; Ware, J et al. (2014) Non-myeloablative conditioning with busulfan before hematopoietic stem cell transplantation leads to phenotypic correction of murine Bernard-Soulier syndrome. J Thromb Haemost 12:1726-32
Zheng, Yongwei; Wang, Alexander W; Yu, Mei et al. (2014) B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia. Blood 123:931-4
Elbatarny, M; Mollah, S; Grabell, J et al. (2014) Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project. Haemophilia 20:831-5
Weiler, Hartmut (2014) Inflammation-associated activation of coagulation and immune regulation by the protein C pathway. Thromb Res 133 Suppl 1:S32-4
Brott, David A; Katein, Anne; Thomas, Heath et al. (2014) Evaluation of von Willebrand factor and von Willebrand factor propeptide in models of vascular endothelial cell activation, perturbation, and/or injury. Toxicol Pathol 42:672-83
Zheng, Yongwei; Yu, Mei; Podd, Andrew et al. (2013) Critical role for mouse marginal zone B cells in PF4/heparin antibody production. Blood 121:3484-92
Qi, Xiaopeng; Hong, Jessie; Chaves, Lee et al. (2013) Antagonistic regulation by the transcription factors C/EBP* and MITF specifies basophil and mast cell fates. Immunity 39:97-110
Tourdot, Benjamin E; Brenner, Michelle K; Keough, Kathleen C et al. (2013) Immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated inhibitory signaling is regulated by sequential phosphorylation mediated by distinct nonreceptor tyrosine kinases: a case study involving PECAM-1. Biochemistry 52:2597-608

Showing the most recent 10 out of 176 publications