The overall vision is to create a detailed understanding of mechanisms that regulate the blood clotting system, with a goal of elucidating the aspects of the clotting machinery that function differentially in hemostasis versus thrombosis. The conceptual framework is that human thrombotic diseases result from an otherwise protective mechanism (immunothrombosis) gone awry. In this view, hemostasis following vascular injury is driven by the prompt exposure of blood to preexisting, natural procoagulants such as tissue factor and collagen that are ubiquitous throughout the body and that induce rapid formation of hemostatic plugs. On the other hand, immunothrombosis is likely triggered and/or greatly enhanced by the elaboration of damage-associated molecular patterns (DAMPs) and pathogen-associate molecular patterns (PAMPs). An important concept is that many of these PAMPs and DAMPs that drive immunothrombosis are potential therapeutic targets that should have little or no involvement in normal hemostasis. In order to achieve this vision, we need to have a much better mechanistic understanding of what regulates blood clotting reactions, and in particular we need to identify and understand the DAMPs that drive thrombosis and coagulopathies. The proposed work will focus on three general areas within this general conceptual framework: elucidating mechanisms by which procoagulant anionic polymers such as polyphosphate (polyP) and nucleic acids trigger regulate blood clotting and inflammation; identifying key structural details that control the function of the tissue factor/factor VIIa complex; and achieving a detailed understanding of how phospholipid bilayers regulate blood clotting reactions. These studies will build on our prior success in this area and will advance the field.

Public Health Relevance

(relevance of this research to public health): Our laboratory is studying recently discovered molecules that contribute to thrombosis?the formation of life- threatening, unwanted blood clots inside arteries or veins. These basic science studies have the potential to lead to new insights into how unwanted blood clots occur in heart attack, stroke and deep vein thrombosis. These studies may allow us to develop new treatments for diseases like thrombosis and hemophilia that are caused by improper functioning of the blood clotting system.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
5R35HL135823-04
Application #
9650625
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Sarkar, Rita
Project Start
2017-08-31
Project End
2024-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Smith, Stephanie A; Wang, Yan; Morrissey, James H (2018) DNA ladders can be used to size polyphosphate resolved by polyacrylamide gel electrophoresis. Electrophoresis 39:2454-2459
Slatter, David A; Percy, Charles L; Allen-Redpath, Keith et al. (2018) Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies. JCI Insight 3:
Mafi, Amirhossein; Abbina, Srinivas; Kalathottukaren, Manu Thomas et al. (2018) Design of Polyphosphate Inhibitors: A Molecular Dynamics Investigation on Polyethylene Glycol-Linked Cationic Binding Groups. Biomacromolecules 19:1358-1367
Smith, Stephanie A; Gajsiewicz, Joshua M; Morrissey, James H (2018) Ability of Polyphosphate and Nucleic Acids to Trigger Blood Clotting: Some Observations and Caveats. Front Med (Lausanne) 5:107
Zilberman-Rudenko, Jevgenia; Reitsma, Stéphanie E; Puy, Cristina et al. (2018) Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo. Arterioscler Thromb Vasc Biol 38:1748-1760
Smith, Stephanie A; Baker, Catherine J; Gajsiewicz, Joshua M et al. (2017) Silica particles contribute to the procoagulant activity of DNA and polyphosphate isolated using commercial kits. Blood 130:88-91