Despite decades of basic and clinical research, thrombosis, a consequence of perturbed hemostasis, remains the major cause of morbidity and mortality in the United States. The topic of this Program Project, currently in its twenty-fifth year, is the regulation of the hemostatic process. Regulated hemostasis insures that following vascular trauma, hemorrhage is rapidly quenched, but at the same time, the fluidity of the blood is maintained. It is clear that both hemostasis and thrombosis are dynamic processes, characterized by the sequential accumulation and removal of newly activated platelets and fibrin at sites of vascular damage. The overall goal of this Program Project is to discover ways in which the dynamic nature of hemostasis and thrombosis can be interrupted for therapeutic benefit. Because of the interests and expertise of the participants in the Program, its projects are focused primarily on platelets. The projects will address the remarkably rapid activation of quiescent platelets, the dynamic nature of platelet plugs, and the use of platelets for targeted drug delivery. The Program Project consists of four projects and one core unit, all based at the University of Pennsylvania. The goals of Project 1 entitled "Controlling allbps Function by Altering Its Energy Landscape," are to gain a thermodynamic understanding of allbps regulation and to use this understanding to develop novel allosteric modulators that attenuate allbpS function. Project 2, entitled "Platelet-Targeted Pro-Urokinase for Thrombolysis," will continue the development of PLT/uPA-T, focusing on its use in the treatment of deep venous thrombosis. PLT/uPA-T is designed to target nascent thrombi while sparing stable mature clots by tethering thrombin-activatab;e urokinase to platelets using single-chain variable region fragments (scFv) of anti-allbps monoclonal antibodies. Project 3, new to the Program Project, is entitled "Phosphatidylinositol Transfer Proteins &Platelet Biology" and addresses the role of Class I phosphatidylinositol transfer proteins in the synthesis of phosphoinositides by platelets. This is a novel topic not previously studied in the context of hemostasis and thrombosis. Project 4, entitled "Subcellular Mechanisms of Platelet Activation," will extend an ongoing project, merging new hypotheses about the platelet signaling network with new models of platelet activation in vivo. Studies will examine the structure of platelet thrombi by testing ideas about the development and contribution of a hierarchical thrombus structure, will consider how the platelet signaling network affects thrombus structure, and will study contact-dependent events arising from molecules present in the junctions between aggregating platelets. The four projects are supported by a single core unit that provides for the common administrative needs of the program.

Public Health Relevance

Heart attack and stroke remain among the leading causes of morbidity and mortality in the United States. The formation of platelet thrombi at sites of vascular damage, such as that caused by atherosclerosis, is the usual precipitating event for both of these processes. The goal of this Program Project has been, and remains, to understand how platelet function is regulated in order to devise more efficacious and safer ways to attenuate platelet accumulation sites at vascular damage, preventing subsequent tissue ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL040387-26A1
Application #
8668266
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
Project Start
1994-06-15
Project End
2019-04-30
Budget Start
2014-05-16
Budget End
2015-04-30
Support Year
26
Fiscal Year
2014
Total Cost
$2,247,186
Indirect Cost
$675,182
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tomaiuolo, Maurizio; Stalker, Timothy J; Welsh, John D et al. (2014) A systems approach to hemostasis: 2. Computational analysis of molecular transport in the thrombus microenvironment. Blood 124:1816-23
Welsh, John D; Stalker, Timothy J; Voronov, Roman et al. (2014) A systems approach to hemostasis: 1. The interdependence of thrombus architecture and agonist movements in the gaps between platelets. Blood 124:1808-15
Lian, Lurong; Suzuki, Aae; Hayes, Vincent et al. (2014) Loss of ATE1-mediated arginylation leads to impaired platelet myosin phosphorylation, clot retraction, and in vivo thrombosis formation. Haematologica 99:554-60
Stalker, Timothy J; Welsh, John D; Tomaiuolo, Maurizio et al. (2014) A systems approach to hemostasis: 3. Thrombus consolidation regulates intrathrombus solute transport and local thrombin activity. Blood 124:1824-31
Stalker, Timothy J; Welsh, John D; Brass, Lawrence F (2014) Shaping the platelet response to vascular injury. Curr Opin Hematol 21:410-7
Kowalska, M Anna; Zhao, Guohua; Zhai, Li et al. (2014) Modulation of protein C activation by histones, platelet factor 4, and heparinoids: new insights into activated protein C formation. Arterioscler Thromb Vasc Biol 34:120-6
Min, Sang H; Suzuki, Aae; Stalker, Timothy J et al. (2014) Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice. Nat Commun 5:4691
Brass, Lawrence F; Tomaiuolo, Maurizio; Stalker, Timothy J (2013) Harnessing the platelet signaling network to produce an optimal hemostatic response. Hematol Oncol Clin North Am 27:381-409
Lu, Qiongyu; Dong, Ningzheng; Wang, Qi et al. (2013) Increased levels of plasma soluble Sema4D in patients with heart failure. PLoS One 8:e64265
Stalker, Timothy J; Traxler, Elizabeth A; Wu, Jie et al. (2013) Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. Blood 121:1875-85

Showing the most recent 10 out of 238 publications