Tatiana V Byzova, Ph.D.
Robert Canova Chair in Angiogenesis Research
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
The major objective of my research program is to fully integrate the mechanistic studies performed at the molecular and cellular levels with complex in vivo models of human diseases to yield a complete understanding of fundamental problems in physiology and pathophysiology. The major research focus of the lab is on the mechanisms governing the pathological and adaptive vasculature development, neoangiogenesis, in adult organisms. This process is crucial for the tissue recovery from ischemia, a response that is triggered in a variety of pathogenic settings including the complications of thrombosis, injury and wound healing, and cancer progression and tumor metastatic spread. At the cellular level, we are interested in endothelial cell biology, therole of inflammatory and other blood cells, including platelets, during neovascularization. To consider neoangiogenesis at a molecular level, my research has emphasized the regulatory functions of extracellular matrix, its cellular receptors, integrins and signaling pathways and the interrelationship between these processes. For our angiogenesis studies, we employ cutting edge animal models, including angiogenesis induced by various tumors, by ischemic conditions in hind limbs, wounds and skin transplants, and by gene transfer of the growth factor of interest. We have established a number of other valuable in vivo models that include wound healing, tumor progression, metastasis and tumor-induced bone remodeling intransgenic/knockout mice, angiogenesis and blood flow analysis, atherosclerosis and thrombosis models.
- Jihad Kaouk, M.D., Urology
- Eric Klein, M.D., Urology
- Brian Rini, M.D., Solid Tumor Oncology
- Andrew Stephenson, M.D., Urology
- Bruce Trapp, Ph.D., Neurosciences
- Dimitrios Davalos, Ph.D., Neurosciences
- Matt Kalaycio, M.D., Hematology Oncology
The Byzova Lab's aim is to understand how blood vessels function in adulthood and development, how normal and healthy vasculature is preserved, and what methods control vascular growth in adults.
Dr. Byzova’s research program is focused on the mechanisms governing the pathological and adaptive vasculature development in adult organisms. Dr. Byzova was trained as a fellow by Dr. Edward Plow, Department Chair of Molecular Cardiology at Cleveland Clinic, who is a key authority in integrin signaling in vascular biology and hemostasis. As a faculty member at Cleveland Clinic, Dr. Byzova learned not only how to carry out rigorous science, but also how to ensure that her projects are clinically important. Dr. Byzova’s lab strives to apply mechanistically oriented research to solve existing problems in patients care as well as to find new interesting directions in translational and clinical research. Their studies are focused on vasculature development, recruitment of inflammatory cells, interactions between growing vasculature and circulating blood cells (including platelets), the role of oxidative processes in regulation of vasculature. They incorporate state-of-the-art animal models of human diseases, including various models of ischemic injury, myocardial infarction, thrombosis, and angiogenesis. Mechanistically, Dr. Byzova’s lab focuses on the role of integrin and integrin-dependent complexes in basic cell migration, endothelial biology and angiogenesis. In their studies on integrin signaling they have identified a new player, Kindlin (Malinin et al., Nature Medicine), which is involved in integrin activation on numerous cell type including endothelium. Besides their interest in the mechanisms and role of integrins in VEGF-driven vascularization, Dr. Byzova’s lab is interested in novel VEGF independent mechanisms of vascularization. They have recently shown that the end products of lipid oxidation are generated during inflammation, and accumulate in wounds, in areas of myocardial infarction and in aging and are able to trigger angiogenesis via TLR2 receptors (West et al., Nature). This distinct pathway also leads to integrin activation and engagement. Thus, in their studies on the role of integrins, they consider both activators of endothelial function, VEGFR2 and TLR2.
ABOUT THE BYZOVA LAB MEMBERS
Dr. Julia Meller (Postdoctoral Research Fellow) joined the Byzova Lab in 2009 after completing her doctoral training with Dr. Martin Schwartz, a distinguished scientist in the field of integrins. The discovery of Kindlins as direct mediators of integrin activation by the Byzova Lab triggered her interest in the field of integrin activation. Her studies involving LADIII patient samples led her to discover novel phenotypical features of Kindlin 3 deficiency. During her subsequent work with an animal model of LADIII, she found a novel role of K3 in the function of microglia cells, leading to her publication entitled ‘Novel aspects of Kindlin-3 function in humans based on a new case of Leukocyte Adhesion Deficiency III (LAD-III)’ (Meller J et al., Journal of Thrombosis and Heamostasis, 2012). Her current project is focused on elucidating the role of Kindlin 3 in the integrin mediated modulation of neural circuits by microglia cells. Dr. Meller has a background in cell biology, signal transduction, and integran activation, having earned her B.S. and M.S. from Ben Gurion University in Isreal, and her Ph.D. from University of Virginia in Charlottesville, Virginia.
Rebecca Cull, M.S. (Research Technologist) joined the Byzova Lab in 2015 after completing her Master’s degree in molecular and cellular biology. Her contributions to the lab span multiple projects, specifically including isolation and staining of whole mount retinas, microscopy and confocal imaging, as well as genotyping for the lab. Ms. Cull has a background in molecular biology, having earned both her B.S. and M.S. from Bowling Green State University in Bowling Green, Ohio.
Dr. Tejasvi Dudiki (Postdoctoral Research Fellow) joined the Byzova Lab in 2015. His primary focus is to decipher the mechanism of selective uptake of tumor-secreted factors by platelets, their transport and release at target sites that promotes cancer metastasis and associated thrombosis. He is also working on understanding the effects of Kindlin-3 protein deficiency on the eye and central nervous system utilizing complex in vivo models of human disease. Dr. Dudiki received his doctoral degree in cellular and molecular biology for his work on the role of serine/threonine phospahatases (PSPs) in reproductive biology. Additionally, he earned a Master’s degree in genetics and a bachelor’s degree in genetics and microbiology.
Dr. Rakhilya Murtazina (Postdoctoral Research Fellow) joined the Byzova Lab in 2015. Her current project is focused on the role of endothelial TLR2 in angiogenesis and hair follicles and the role microglial of kindlin 3 in normal and pathological brain physiology. Dr. Murtazina has a background in cell biology, physiology, and biochemistry, having earned her B.S. and M.S. and Ph.D. from M.V. Lomonosov Moscow State University in Russia.
Dr. Saswat K. Bal (Postdoctoral Research Fellow) joined the Byzova Lab in 2015. His current project is focused on elucidating the role of integrins in aortic root inflammation. After completing his doctoral training with Dr. Chinmay K. Mukhopadhyay, he studied the mechanisms by which Leishmania donovani, a protozoan parasite, sequesters iron from the macrophages for its survival. Dr. Bal has a background in molecular biology, cell biology, and infection biology. He earned his M.S. degree from Utkal University in India and his Ph.D. degree from Jawaharlal Nehru University in New Delhi, India.
Samantha Stefl, M.S. (Research Technologist) joined the Byzova Lab in 2015. Assisting with a range of projects in the lab, her contributions include microglia isolation, tumor isolation, mice colony management, and cell culture. Ms. Stefl earned her Master’s degree in molecular and cellular biology from the University of Toledo, where she studied the roles of Mixed Lineage Kinases and interferons in viral detection pathways. She earned her Bachelor’s degree from Kent State University where she studied the role of PKC delta in ischemic stroke.
Dr. Huan Liu (Postdoctoral Fellow) joined the Byzova Lab in 2016 after earning her Ph.D. in cell biology in 2015. Her current project focuses on the mechanism of kindlin3 and integrin organizing inside-out and outside-in signals and coordinating cell movement, and the function of integrin in angiogenesis. Dr. Liu has a background in molecular and cell biology, signal transduction, tumorigenesis, metastasis, stem cell, and epigenetics, having receiving her Ph.D, from Zhejiang University in China.
We have demonstrated that Akt pathway is crucial for vascular function and vascular integrity in adults. Interference with this pathway in endothelial cells leads to a loss of smooth muscle cells, vasculature deterioration, and poor tissue perfusion. This causes organ dysfunction, first of all cardiac abnormalities and retina degeneration. Kerr BA … Byzova TV Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium Nature Communications (2016)
We have demonstrated a novel mechanism of recognition and clearance of oxidized lipid metabolites, which were previously believed to be end-products of oxidative process. These oxidized lipid metabolites accumulate in atherosclerotic lesions of blood vessels, including aortas (shown on the cover). The study shows that high levels of oxidized products found in pathologies, including atherosclerosis and cancer, might be due to their insufficient clearance by macrophages. Kim YW … Byzova TV Receptor-Mediated Mechanism Controlling Tissue Levels of Bioactive Lipid Oxidation Products
Circulation Research (2015)
Tumor growth requires additional blood vessel growth or angiogenesis.
We have found that platelets are required for tumor angiogenesis.
Platelets control blood vessel growth (red cells by stimulating bone marrow-derived cell recruitment to tumors (green cells).
Feng W … TV Byzova A Novel Role for Platelet Secretion in Angiogenesis: Mediating Bone Marrow-derived
Cell Mobilization and Homing
We have demonstrated that reducing
Akt activity might alleviate heart
complications and mortality
associated with atherosclerosis and
This image shows an artist's depiction
of an atherosclerotic plaque and was
inspired by one of our high-profile
Kerr BA … TV Byzova
Interference with akt signaling
protects against myocardial infarction
and death by limiting the
consequences of oxidative stress
Science Signaling (2013)
New blood vessel formation, or angiogenesis, is regulated by the expression of integrins, such as αvβ3 and αvβ5, on endothelial cells, platelets, fibroblasts and smooth muscle cells (A). In addition, integrins αvβ3 and αvβ5 control the movement of tumor cells into the blood stream and their arrest at future metastatic sites (B). The αvβ3 is located on bone marrow-derived cells which are recruited to tumors to support tumor growth. Kerr, BA and TV Byzova Integrin Alpha V (ITGAV) Encyclopedia of Signaling Molecules Ed. Sangdun Choi Springer (2013)
Selected Publications (2015-present):
Xiong L, McCoy M, Komuro H, West XZ, Yakubenko V, Gao D, Dudiki T, Milo A, Chen J, Podrez EA, Trapp B, Byzova TV.(2022) Inflammation-dependent oxidative stress metabolites as a hallmark of amyotrophic lateral sclerosis. Free Radic Biol Med. 178:125-133. PMID: 34871763; PMCID: PMC8744315
McCoy MG, Nascimento DW, Veleeparambil M, Murtazina R, Gao D, Tkachenko S, Podrez E, Byzova TV. (2021) Endothelial TLR2 promotes proangiogenic immune cell recruitment and tumor angiogenesis. Sci Signal. 14(666):eabc5371. PMID: 33986920; PMCID: PMC8112454
Kerr BA, Harris KS, Shi L, Willey JS, Soto-Pantoja DR, Byzova TV. (2021) Platelet TSP-1 controls prostate cancer-induced osteoclast differentiation and bone marrow-derived cell mobilization through TGFβ-1. Am J Clin Exp Urol. 9(1):18-31. PMID: 33816691; PMCID: PMC8012834
Dudiki T, Mahajan G, Liu H, Zhevlakova I, Bertagnolli C, Nascimento DW, Kothapalli CR, Byzova TV. (2021) Kindlin3 regulates biophysical properties and mechanics of membrane to cortex attachment. Cell Mol Life Sci. 2021 Mar 30. PMID: 33783564
Biswas S, Gao D, Altemus JB, Rekhi UR, Chang E, Febbraio M, Byzova TV, Podrez EA. (2021) Circulating CD36 is increased in hyperlipidemic mice: Cellular sources and triggers of release. Free Radic Biol Med. 168:180-188. PMID: 33775772
Kerr BA, Shi L, Jinnah AH, Harris KS, Willey JS, Lennon DP, Caplan AI, Byzova TV. (2021) Kindlin-3 mutation in mesenchymal stem cells results in enhanced chondrogenesis. Exp Cell Res. 399(2):112456. PMID: 33417921; PMCID: PMC7874523
Podrez EA, Byzova TV. (2020) Remodeling vasculature to avoid blindness. Science 369(6506):919-920. PMID: 32820112
Liu H, Zhu L, Dudiki T, Gabanic B, Good L, Podrez EA, Cherepanova OA, Qin J, Byzova TV. (2020) Macrophage Migration and Phagocytosis Are Controlled by Kindlin-3's Link to the Cytoskeleton. J Immunol. 204(7):1954-1967. PMID: 32094207
Dudiki T, Meller J, Mahajan G, Liu H, Zhevlakova I, Stefl S, Witherow C, Podrez E, Kothapalli CR, Byzova TV. (2020) Microglia control vascular architecture via a TGFβ1 dependent paracrine mechanism linked to tissue mechanics. Nat Commun. 11(1):986. PMID: 32080187; PMCID: PMC7033106
Gao D, Ashraf MZ, Zhang L, Kar NS, Byzova TV, Podrez EA. (2020) Cross-linking modifications of HDL apoproteins by oxidized phospholipids: Structural characterization, in vivo detection, and functional implications. J Biol Chem. 295(7):1973-1984. PMID: 31907281; PMCID: PMC7029106
Zhu L, Liu H, Lu F, Yang J, Byzova TV, Qin J. (2019) Structural Basis of Paxillin Recruitment by Kindlin-2 in Regulating Cell Adhesion. Structure. 27(11):1686-1697.e5. PMID: 31590942; PMCID: PMC6894617
Cui K, Podolnikova NP, Bailey W, Szmuc E, Podrez EA, Byzova TV, Yakubenko VP. (2019) Inhibition of integrin αDβ2-mediated macrophage adhesion to end product of docosahexaenoic acid (DHA) oxidation prevents macrophage accumulation during inflammation. J Biol Chem. 294(39):14370-14382. PMID: 31395659; PMCID: PMC6768641
Yakubenko VP, Cui K, Ardell CL, Brown KE, West XZ, Gao D, Stefl S, Salomon RG, Podrez EA, Byzova TV. (2018) Oxidative modifications of extracellular matrix promote the second wave of inflammation via β2 integrins. Blood. 132(1):78-88. PMID: 29724896; PMCID: PMC6034644
Zhu L, Yang J, Bromberger T, Holly A, Lu F, Liu H, Sun K, Klapproth S, Hirbawi J, Byzova TV, Plow EF, Moser M, Qin J. (2017) Structure of Rap1b bound to talin reveals a pathway for triggering integrin activation. Nat Commun. 8(1):1744. PMID: 29170462; PMCID: PMC5701058
Feng W, Valiyaveettil M, Dudiki T, Mahabeleshwar GH, Andre P, Podrez EA, Byzova TV. (2017) β3 phosphorylation of platelet αIIbβ3 is crucial for stability of arterial thrombus and microparticle formation in vivo. Thromb J. 15:22. PMID: 28860945; PMCID: PMC5576334
Biswas S, Zimman A, Gao D, Byzova TV, Podrez EA. (2017) TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia. Circ Res. 121(8):951-962. PMID: 28775078; PMCID: PMC5623081
Meller J, Chen Z, Dudiki T, Cull RM, Murtazina R, Bal SK, Pluskota E, Stefl S, Plow EF, Trapp BD, Byzova TV. (2017) Integrin-Kindlin3 requirements for microglial motility in vivo are distinct from those for macrophages. JCI Insight. 2(11). pii: 93002. PMID: 28570266; PMCID: PMC5453700
Yakubenko VP, Byzova TV. (2017) Biological and pathophysiological roles of end-products of DHA oxidation. Biochim Biophys Acta Mol Cell Biol Lipids. 1862(4):407-415. PMID: 27713004; PMCID: PMC5360178
Ding L, Zhang L, Biswas S, Schugar RC, Brown JM, Byzova T, Podrez E. (2017) Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling. JCI Insight. 2(22). pii: 95687. PMID: 29202451; PMCID: PMC5752373
Ding L, Zhang L, Kim M, Byzova T, Podrez E. (2017) Akt3 kinase suppresses pinocytosis of low-density lipoprotein by macrophages via a novel WNK/SGK1/Cdc42 protein pathway. J Biol Chem. 292(22):9283-9293. PMID: 28389565; PMCID: PMC5454109
Byzova TV. (2016) "Fishing" out the real VEGFs. Blood. 128(19):2283-2284. PMID: 28829753; PMCID: PMC5106111
Gao F, Artham S, Sabbineni H, Al-Azayzih A, Peng XD, Hay N, Adams RH, Byzova TV, Somanath PR. (2016) Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover. Cell Mol Life Sci. 73(20):3917-33. PMID: 27113546; PMCID: PMC5023469
Biswas S, Xin L, Panigrahi S, Zimman A, Wang H, Yakubenko VP, Byzova TV, Salomon RG, Podrez EA. (2016) Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE-/- mice and activate platelets via TLR2. Blood. 127(21):2618-29. PMID: 27015965; PMCID: PMC4882806
Kerr BA, West XZ, Kim YW, Zhao Y, Tischenko M, Cull RM, Phares TW, Peng XD, Bernier-Latmani J, Petrova TV, Adams RH, Hay N, Naga Prasad SV, Byzova TV. (2016) Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium. Nat Commun. 7:10960. PMID: 26971877; PMCID: PMC4793084
Podrez EA, Byzova TV. (2016) Prothrombotic lipoprotein patterns in stroke. Blood. 127(10):1221-2. PMID: 26965920; PMCID: PMC4786832
Kim YW, Yakubenko VP, West XZ, Gugiu GB, Renganathan K, Biswas S, Gao D, Crabb JW, Salomon RG, Podrez EA, Byzova TV. (2015) Receptor-Mediated Mechanism Controlling Tissue Levels of Bioactive Lipid Oxidation Products. Circ Res. 117(4):321-32. PMID: 25966710; PMCID: PMC4522201
Bialkowska K, Byzova TV, Plow EF. (2015) Site-specific phosphorylation of kindlin-3 protein regulates its capacity to control cellular responses mediated by integrin αIIbβ3. J Biol Chem. 290(10):6226-42. PMID: 25609252; PMCID: PMC4358261
Kerr BA, Miocinovic R, Smith AK, West XZ, Watts KE, Alzayed AW, Klink JC, Mir MC, Sturey T, Hansel DE, Heston WD, Stephenson AJ, Klein EA, Byzova TV. (2015)CD117⁺ cells in the circulation are predictive of advanced prostate cancer. Oncotarget. 6(3):1889-97. PMID: 25595903; PMCID: PMC4359340
Meller J, Rogozin IB, Poliakov E, Meller N, Bedanov-Pack M, Plow EF, Qin J, Podrez EA, Byzova TV. (2015) Emergence and subsequent functional specialization of kindlins during evolution of cell adhesiveness. Mol Biol Cell. 26(4):786-96. PMID: 25540429; PMCID: PMC4325847
|US Patent||Patent Title||Issue Date||First-Named Inventor|
|8,080,252||Compounds and Methods of Modulating Angiogenesis||12/20/2011||Tatiana V. Byzova, Ph.D.|
|[Pending]||Use of Platelets As a Source of Prostate Cancer Biomarkers||Tatiana V. Byzova, Ph.D.|
Dr. Byzova found that microglia sense and respond to changes in tissue stiffness, a hallmark of many neurological and retinal disorders, and identified a related signaling cascade that may be targeted to correct microglial response and potentially treat the associated disorders.