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Principal Investigator: Matthew J. Flick
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $734,117
Funding agency: National Heart Lung and Blood Institute
SUMMARY/SCOPE OF WORK
BACKGROUND AND SIGNIFICANCE: Thrombotic diseases are the leading cause of death and disability
worldwide. Genetic, environmental, and pharmacological factors, as well as acute and chronic inflammatory
diseases, are linked to exacerbated thrombosis. Despite this heterogeneity of etiology and risk factors,
thrombosis pathogenesis converges on a common pathway culminating in the conversion of soluble fibrinogen
to an insoluble fibrin matrix that serves as the primary structural component of blood clots. However, there are
currently no therapeutic approaches that directly modulate fibrinogen.
RATIONALE: Thrombosis risk and severity are increased substantially with elevated circulating fibrinogen levels
and other perturbations that promote the formation of a dense fibrin network that is resistant to degradation. This
proposal is based on the concept that fibrin(ogen) can be directly targeted to produce porous fibrin clot structures
with poor red blood cell retention and enhanced susceptibility to fibrinolysis with the ultimate goal of reducing
thrombosis across diverse settings regardless of other confounding sequelae. The central hypothesis is that
specific and selective reduction of circulating fibrinogen levels or directed suppression of fibrin matrix formation
significantly protects against venous and arterial thrombosis while maintaining hemostatic potential.
SPECIFIC AIMS: Innovative studies will be performed using (i) a newly developed lipid nanoparticle delivery
system of a small interfering RNA (siRNA) that knocks down fibrinogen to any desired target level and (ii) genetic
and pharmacological strategies (mRNA delivery) utilizing a customized fibrinogen variant (fibrinogenLOCK) that
suppresses fibrin polymerization. These approaches will be used to uncover the contributions of fibrinogen and
fibrin matrix formation in the development of venous and arterial thrombosis as well as to hemostasis and platelet
plug formation. The specific aims are to: (1) Determine the changes in venous and arterial thrombus formation
following targeted reduction in circulating fibrinogen or selective suppression of fibrin matrix formation; (2)
Determine qualitative and quantitative changes in bleeding and platelet plug formation during hemostatic
challenges following fibrinogen reduction or suppression of fibrin matrix formation; (3) Determine the efficacy of
fibrinogen reduction or introduction of fibrinogenLOCK in mitigating thrombosis during endotoxemia (acute
inflammation) and sickle cell disease (chronic inflammatory disease).
EXPECTED OUTCOMES AND DELIVERABLES: This work will provide novel mechanistic insight into how
quantitative and qualitative changes in circulating fibrinogen or fibrin matrix formation alters thrombogenesis.
Moreover, the proposed studies will provide essential preclinical data on a novel management strategy for
thrombotic disease across diverse etiologies. We expect to demonstrate that knocking down fibrinogen or
introducing a polymerization-suppressing fibrinogen mutant mitigates thrombosis without impairing hemostasis,
even in the context of pro-thrombotic acute and chronic inflammatory diseases.
Terms: <Acute><Address><Afibrinogenemia><Age><Apoplexy><Bleeding><Blood Clotting><Blood Coagulation Factor I><Blood Coagulation Factor II><Blood Coagulation Factor One><Blood Factor One><Blood Plasma><Blood Platelets><Blood coagulation><Blood erythrocyte><Brain Vascular Accident><Carotid Artery Thrombosis><Carotid Thrombosis><Causality><Cause of Death><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chronic><Clotting><Coagulation><Coagulation Factor I><Coagulation Factor II><Coagulation Factor One><Coagulation Process><Congenital afibrinogenemia><Congenital hypofibrinogenemia><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Creativeness><Data><Deep Vein Thrombosis><Deep-Venous Thrombosis><Development><Differentiation Reversal Factor><Disease><Disorder><Endotoxemia><Erythrocytes><Erythrocytic><Etiology><Factor I><Factor I Deficiency><Factor II><Factor One><Fibrin><Fibrinogen><Fibrinogen Deficiency><Fibrinolyses><Fibrinolysis><Fostering><Fracture><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Gestation><Goals><Hb SS disease><HbSS disease><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><Hemorrhage><Hemostasis><Hemostatic Agents><Hemostatic function><Hemostatics><Hereditary factor I deficiency disease><Hereditary hypofibrinogenemia><Heterogeneity><Impairment><Incidence><Infection><Inferior Vena Cava><Inferior vena cava structure><Inflammation><Inflammatory><Knowledge><Link><Liver><Marrow erythrocyte><Marrow platelet><Mice><Mice Mammals><Modeling><Morbidity><Morbidity - disease rate><Murine><Mus><Mutation><Oral Contraceptives><Outcome><Pathogenesis><Pathologic><Pathology><Pathway interactions><Plasma><Plasma Serum><Platelets><Polymers><Porosity><Predisposition><Pregnancy><Process><Proteins><Prothrombin><Public Health><Pulmonary Embolism><Red Blood Cells><Red Cell><Research><Resistance><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Severities><Short interfering RNA><Sickle Cell Anemia><Small Interfering RNA><Smoking><Stroke><Structure><Susceptibility><System><Testing><Therapeutic><Therapeutic Uses><Thrombase><Thrombin><Thrombocytes><Thrombosis><Thrombus><Trauma><Variant><Variation><Venous><Work><ages><atherosclerotic coronary disease><birth control pill><blood corpuscles><blood loss><bone fracture><brain attack><causation><cerebral vascular accident><cerebrovascular accident><chronic inflammatory disease><clinical relevance><clinically relevant><coronary arterial disease><creativity><deliver mRNA><deliver messenger RNA><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for mRNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><determine efficacy><developmental><disability><disease causation><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><fibrinogenase><genome mutation><hepatic body system><hepatic organ system><innovate><innovation><innovative><insight><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><mRNA delivery><messenger RNA delivery><monomer><mortality><mutant><nano particle delivery><nanoparticle delivered><nanoparticle delivery><novel><pathway><pharmacologic><polymer><polymeric><polymerization><pre-clinical><preclinical><preservation><prevent><preventing><programs><prophylactic><resistant><short interfering RNA delivery><siRNA><siRNA delivery><sickle cell disease><sickle cell disorder><sickle disease><sicklemia><small interfering RNA delivery><stroked><strokes><targeted agent><thromboembolic complications><thrombogenesis><thrombogenicity><thromboinflammation><thromboinflammatory><thrombolysis><thrombosis complications><thrombotic><thrombotic complications><thrombotic disease><thrombotic disorder><tool><translational opportunities><translational potential><venous thromboembolism>