Komissarov, Andrey, Ph.D.
M.S., Chemistry of Natural Compounds, 1980, Moscow State University, Moscow, USSR.
Ph.D., Chemistry of Natural Compounds, 1988, Moscow State University, Moscow, USSR.
- Modulation of the serpin/proteinase interaction.
- Molecular mechanisms of fibrinolysis in vivo.
- Increasing the efficacy of fibrinolytic therapy.
- Bio-analytic approaches to personalized therapy.
- Novel anti-thrombotic drugs.
Vascular occlusion due to the pathological accumulation of blood components(platelets, fibrinogen, etc.) in the circulation, results in thrombotic disease, which is the number one killer in the industrialized world. Plasminogen activator inhibitor 1 (PAI-1) is a serpin that plays an important role in the control of normal and pathological thrombosis (clotting) and fibrinolysis (clot breakdown). PAI-1 is a mechanism based inhibitor of urokinase (uPA) and tissue type (tPA) plasminogen activators. PAI-1 prevents the formation of plasmin, thus inhibitingthe fibrinolytic system and promoting thrombosis in the vasculature and extravascular fibrin deposition seen in acute lung and pleural injury, lung, and cystic fibrosis, etc. High levels of PAI-1 are associated with a number of life threatening conditions such as myocardial infarction, sepsis, atherosclerosis, angina pectoris, pleural and acute lung injury and correlate with unfavorable outcomes in disseminated intravascular coagulation (sepsis), acute lung and pleural injury, and in a number of malignancies. Evaluation of the serpin reaction and mechanisms of PAI-1 neutralization, and the search for new PAI-1 inhibitors results in the improvement of fibrinolytic therapy. Understanding the molecular mechanisms governing fibrinolysis is an approach to personalizing fibrinolytic therapy and predicting its outcome based on the analysis of the bio-samples from a patient.
Current Projects/Lay Summaries:
I. Study of serpin/proteinase interactions and intermolecular mechanisms of modulation of serpin activity and stability. Current studies include understanding the mechanisms that control (i) the specificity of the serpin reaction; (ii) the modulation of PAI-1 activity via intermolecular interactions; (iii) the contribution of exosite interactions to serpin/proteinase reactions; (iv) thespontaneous inactivation of PAI-1. Recent results can be found in the references below: Papers 2, 6, 7, and Abstract 6.
II. Targeting PAI-1 in vivo to increase the efficacy of fibrinolytic therapy. Recently, we have validated active PAI-1 as a molecular target for fibrinolytic therapy in an animal model of pleural fibrosis (Paper 3, Abstract 8). A mechanism that controls the efficacy of fibrinolytic therapy with prourokinase (scuPA) has been proposed and evaluated (Paper 1; Abstract 7). Several intermolecular mechanisms of PAI-1 neutralization previously characterized in vitro were tested in vivo to determine the contribution of active PAI-1 to the efficacy of fibrinolytic therapy (Abstracts 2, 5). Targeting PAI-1 significantly improves the outcomes of fibrinolytic therapy with both scuPA and sctPA.
III. Bio-analytic approaches to personalized fibrinolytic therapy. Fibrinolytic therapy is focused on the activation of endogenous plasminogen to plasmin, providing sustained fibrinolytic activity. Accumulating data demonstrate that while the basic mechanisms governing endogenous fibrinolytic activity could be similar even between different species (Papers 1, 4; Abstracts 1, 4), their different manifestation in individuals could dramatically affect the outcome of fibrinolytic therapy. This project aims to develop an algorithm that would allow us to predict the results of fibrinolytic therapy for an individual, based on the analysis of a pattern of molecular signatures in bio-samples.
IV. Design and characterization of new inhibitors of PAI-1. At present, monoclonal antibodies (mAbs) are the most specific and selective inhibitors of PAI-1. However, therapeutic use favors the search for small (LMW) molecules that inhibit PAI-1 with similar efficacy. Our fundamental knowledge of serpin mechanisms builds a foundation for the development of new PAI-1 inhibitors, and their testing in animal models. Known mechanisms of PAI-1 inactivation are employed for (i) combinatorial selection of peptides specific for the epitopes of PAI-1 neutralizing mAbs, (ii) studies of additivity between different intermolecular mechanisms affecting PAI-1 activity, (iii) further minimization of PAI-1-specific ligands mAb (150 KDa) → Fab (40 KDa) → scFv (20 KDa) → peptide (1-2KDa)→ LMW inhibitors (0.5-1.5 KDa), and (iv) the generation and testing of new multivalent modulators of PAI-1.
Published Papers, 2011-2013:
- Komissarov AA, Florova G, Azghani A., Karandashova S, Kurdowska AK., Idell, S. 2013. Active α-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with tetracycline-induced pleural injury and in human pleural fluids. Am. J. Physiol. Lung Cell Mol. Physiol., in press.
- Florova G, Karandashova S, Declerck PJ, Idell S, Komissarov AA. 2013. Remarkable Stabilization of Plasminogen Activator Inhibitor 1 in a "Molecular Sandwich" Complex. Biochemistry. 2013 Jun 4. [Epub ahead of print].
- Komissarov A A., Stankowska D, Krupa A, Fudala R, Florova G, Florence J, Fol M, Allen TC, Idell, S, Matthay MA, et al. 2012. Novel aspects of urokinase function in the injured lung: role of alpha2-macroglobulin. Am J Physiol Lung Cell Mol Physiol. 2012 Dec 15;303(12):L1037-45. doi: 10.1152/ajplung.00117.2012. Epub 2012 Oct 12.
- Karandashova, S., Florova,G, Azghani, A, Komissarov A,Koenig K, Tucker TA, Allen, TC, Stewart K, Tvinnereim A, Idell S. 2012. Intrapleural Adenoviral Delivery of Human PAI-1 Exacerbates TCN-Induced Pleural Injury in Rabbits. Am J Respir Cell Mol Biol. 2013 Jan;48(1):44-52. doi: 10.1165/rcmb.2012-0183OC. Epub 2012 Sep 20.
- Tucker, T.A, Williams L, Koenig, K, Kothari H, Komissarov AA, Florova G, Mazar AP, Allen TC, Bdeir K, Rao LVM, et al. 2012. Lipoprotein receptor-related protein 1 regulates collagen 1 expression, proteolysis, and migration in human pleural mesothelial cells. Am.J.Respir.Cell Mol.Biol. 46:196-206.
- Komissarov AA, Florova G, Idell S. 2011. Effects of extracellular DNA on plasminogen activation and fibrinolysis. J.Biol.Chem. 286:41949-41962.
- Sen P, Komissarov AA, Florova G, Idell S, Pendurthi UR, Rao LVM. 2011. Plasminogen activator inhibitor-1 inhibits factor VIIa bound to tissue factor. J.Thromb.Haemost. 9:531-539.
- Midde KK., Batchinsky AI, Cancio LC, Shetty S, Komissarov AA, Florova G, Walker, III KP, Koenig K, Chroneos ZC, Allen T, et al. 2011. Wood bark smoke induces lung and pleural plasminogen activator inhibitor 1 and stabilizes its mRNA in porcine lung cells. Shock 36:128-137.
Published Abstracts 2011-2013:
- Komissarov AA, Florova G, Schaefer C, Rahman NM, Lee YCG, Idell S. 2013. Pleural Fluids Collected During The Second Multicenter Intrapleural Sepsis Trial (MIST2) Demonstrate Highly Variable Fibrinolytic Potential Prior To The Treatment And Endogenous Fibrinolytic Activity Depletion During IntrapleuralFibrinolytic Therapy, Am. J. Respir. Crit. Care Med. 187;2013:A4313
- Komissarov AA, Florova G, Azghani A, Karandashova S, Schaefer C, Stewart K, Declerck PJ, Idell S. 2013. NIH CADET 1: Elucidation Of Effective New Strategies For Fibrinolytic Therapy In Tetracycline Induced Pleural Injury In Rabbits, Am. J. Respir. Crit. Care Med. 187;2013:A4312
- Florova, G, Komissarov AA, Azghani A, SSchaefer C, Karandashova S, Stewart-Evans K, Hadden WA, Idell S. 2013. Rapid Inactivation Of Intrapleural Tissue Plasminogen Activator In PasteurellaMultocida Induced Empyema In Rabbits, Am. J. Respir. Crit. Care Med. 187;2013:A4311
- Komissarov AA, Florova G, Azghani A, Karandashova S, Idell S. 2012. High Levels Of Extracelular DNA In Pleural Fluids Of Animals And Patients With Empyema Suppress Fibrinolysis. Am. J. Respir. Crit. Care Med. 185:A1580.
- Komissarov AA, Florova G, Azghani A, Karandashova S, Stewart K, Tvinnereim A, Declerck PJ, Idell S. 2012. Plasminogen Activator Inhibitor 1 Targeting Interventions In The Treatment Of Rabbits With Tetracycline-Induced Pleurodesis. Am. J. Respir. Crit. Care Med. 185:A1571.
- Florova G, Idell S, Komissarov AA. 2012. Remarkable Stabilization Of Active Plasminogen Activator Inhibitor 1/Vitronectin By An Inactive Urokinase Mutant. Am. J. Respir. Crit. Care Med. 185:A6789.
- Komissarov AA., Florova G, Azghani A, Karandashova S, Stewart K, Idell S. 2011. Single Chain Urokinase Yields Relatively Low Grade Fibrinolytic Activity And As More Bioavailable Than Tissue Type Plasminogen Activator In Pleural Fluids Of Rabbits With Tetracycline-Induced Pleurodesis. Am. J. Respir. Crit. Care Med. 183:A2366.
- Karandashova, S, Florova G, Tucker T,Azghani A, Allen T, Stewart K, Komissarov AA, Tvinnereim A, Koenig K, Idell S. 2011. Adenovirus-Mediated Delivery Of High Levels Of Plasminogen Activator Inhibitor 1 Activity To The Pleural Space Exacerbates Fibrotic Injury In Rabbits With Tetracycline-Induced Pleural Injury. Am. J. Respir. Crit. Care Med. 183:A2367.
- Tucker, TA, Williams L, Koenig K, Kothari H Komissarov AA, Florova G, Mazar AP, Rao LVM, Idell S. 2011. Lrp1 Regulates Urokinase Receptor-Dependent Pathophysiologic Responses Of Human Pleural Mesothelial Cells. Am. J. Respir. Crit. Care Med. 183:A3485