Novel regulation of fibrinogen expression and function

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

Abstract

PROJECT SUMMARY Fibrinogen is a highly-conserved 340 kDa glycoprotein that circulates in the blood of vertebrate species at 2-4 mg/mL. Under homeostatic conditions, fibrinogen is synthesized primarily in the liver as a hexameric homodimer comprised of 2 Aα, 2 Bβ, and 2 γ polypeptide chains. In addition to a well-characterized role in thrombosis and hemostasis, fibrinogen is an acute phase reactant that links the hemostatic system to the inflammatory response. Highly elevated plasma fibrinogen concentrations are observed in multiple settings of injury and infection as well as in cancer, cardiovascular and metabolic diseases, and pregnancy. Fibrinogen contains binding domains for leukocyte integrins, and prior studies have suggested that fibrin(ogen) is a pro- inflammatory molecule that coordinates leukocytes recruitment, adhesion, and activation in multiple settings of tissue injury. However, there are major gaps in our understanding of the role of fibrinogen as an acute phase reactant and pro-inflammatory molecule that must be addressed before fibrinogen can be safely and specifically targeted in humans. Overview of research and goals for the next 5 years: The Poole lab opened in October 2022 with the long-term goal of identifying the role of blood coagulation factors as pro-inflammatory or pro-repair signaling molecules. This proposal builds on the expertise of the Poole lab, resources and assays we utilize to study fibrinogen, and the expertise of our collaborators to address fundamental unanswered questions about the pro-inflammatory properties of fibrinogen in the broad context of injury and inflammation. We pursue key scientific questions such as: 1) How are plasma fibrinogen levels regulated in the acute phase response? Our studies will identify the cellular source of fibrinogen in settings of acute inflammation, chronic metabolic disease, and pregnancy. Furthermore, we will identify the molecular signaling events driving acute phase induction of fibrinogen synthesis. Finally, the mechanisms regulating removal of fibrinogen from circulation (i.e., catabolism) under both homeostatic and pathophysiologic conditions are unknown. We will identify the relevant cell type(s) and receptor(s) that mediate fibrinogen clearance. 2) How is fibrin(ogen) deposited in an injured tissue to enable leukocyte interactions? Extravascular fibrin(ogen) deposits are characteristic of multiple disease states. Our studies will define the mechanism of extravascular fibrin(ogen) accumulation, including the contribution of local synthesis. Furthermore, the fibrinogen molecule is susceptible to multiple post-translational modifications in the setting of disease that can affect its structure and function as a clotting protein. However, the impact of these post-translational modifications on fibrinogen's inflammatory activities are unknown. We will determine the impact of relevant post-translational modifications on leukocyte adhesion and activation. Our group will use novel in vivo and in vitro approaches to address these fundamental questions regarding the inflammatory functions of fibrinogen, thereby enabling the discovery of safe and selective therapies to target fibrinogen in disease.