Owens Lab

The Owens Lab

For more information on all of our members, just click on the left!

Owens Lab


Gary Owens, Ph.D.
Principle Investigator

gko@virginia.edu

Gary K. Owens, Ph.D is a Professor in the Departments of Molecular Physiology and Biological Physics and the Department of Medicine, Division of Cardiology. Dr. Owens also is the Director of the Robert M. Berne Cardiovascular Research Center.


Olga A. Cherepanova, PhD
Assistant Professor of Research/Lab Manager

oac4x@virginia.edu

My long-term scientific interest is in elucidating molecular mechanisms responsible for the phenotypic transition of vascular cells, including smooth muscle cells (SMCs), macrophages and endothelial cells (ECs) during atherogenesis, as well as, mechanisms responsible for migration, proliferation and extracellular matrix synthesis by phenotypically modulated vascular cells.

Project 1. Role of the embryonic stem cell pluripotency factor OCT4 in the regulation of phenotypic transition of vascular cells after vascular injury, under the contexts of hyperlipidemia and cancer.

Recently, we found that the embryonic stem cell factor OCT4 plays an athero-protective role in SMCs by regulating SMC phenotypic transition, including migration and SMC investment into fibrous cap {Cherepanova et al., Nature Med, 2016}.
The overall goal of current project is to test if activation of the pluripotency factor Oct4 within ECs plays a key functional role during atherosclerosis development through regulation of EC activation and dysfunction, including EC-monocyte adhesion, Endo-MT and EC migration.

Project 2. Development of an anti-oxidized phospholipid neutralizing antibody as an atheroprotective therapeutic agent.

Oxidized phospholipids (OxPL), such as oxidized PAPC (1-palmitoil-2-arachodonoyl-sn-glycero-3-phosphorylcholine) and its derivatives have been shown to be the principal biologically active components of minimally oxidized LDL, whose role in cardiovascular diseases is well recognized including activation of inflammatory processes within the major cell types in the disease including endothelial cells, SMCs and macrophages. I have recently generated an anti-oxidized phospholipid (oxPL) autoantibody (10C12) that demonstrates potent OxPL neutralizing activity in vitro, as well as the ability to inhibit macrophage accumulation within arteries of atherosclerotic ApoE KO mice fed a high fat diet for 4 weeks. The overall goal of current project is to test whether this 10C12 anti-OxPL antibody can decrease and/or reverse development of atherosclerosis in late stages of the disease since this would mimic likely clinical paradigms.

Project 3. “Role of the SMC-derived extracellular matrix in atherosclerosis”

As a graduate student, I studied extracellular matrix and its role in skin wound healing. The goal of this project is to determine if phenotypically modulated SMC-derived extracellular matrix-related genes play a functional role during atherosclerosis and elucidate molecular mechanisms required for this. I have shown that oxidized phospholipids significantly induced expression and synthesis of several MMPs and extracellular matrix proteins including collagens type VIII and XV in vascular SMC and this newly synthesized extracellular matrix in turn plays important role in phenotypic switching of smooth muscle cells that is related to cardiovascular diseases such as atherosclerosis and restinosis.

Selected Publications:

  • Durgin B, Cherepanova O.A., Gomez D, Karaoli T, Alencar GF, Butcher J, Zhou Y-Q, Bendeck M, Isakson B, Owens GK, Connelly JJ. "Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions", AJP Heart, 2017 (Published on-line - DOI: 10.1152/ajpheart.00029.2017).
  • Cherepanova O.A., Gomez D, Shankman LS, Swiatlowska P, Williams J, Sarmento OF, Alencar FG, Hess DL, Bevard MH, Greene ES, Murgai M, Turner SD, Geng Y-J, Bekiranov S, Connelly JJ, Tomilin A, Owens GK. “Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective”. Nature Medicine, 2016, 22, 657.
  • Shankman LS, Gomez D, Cherepanova O.A., Salmon M, Alencar FG, Haskins RH, Swiatlowska P, Newman AAC, Greene ES, Straub AC, Isakson B, Randolph GJ, Owens GK “KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis”, Nature Medicine 2015, 21, 628-637.
  • Murgai M, Tomas J., Cherepanova O.A., Pathak V, Rekosh D, Owens GK. 2013. Infection of tumor cells with Xenotrophic MLVs promotes the formation of immature blood vessels. J Retrovirology 10: 34.
  • Connelly J.J., Cherepanova O.A., Doss J.F., Karaoli T., Lillard T., Markunas C., Nelson S., Crosslin D.R., Wang T., Ellis P.D., Langford C.F., Haynes T., Seo D., Goldschmidt-Clermont P.J., Shah S.H., Kraus W., , Hauser E.R., Gregory S.G. 2013. Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. Hum Mol Gen 22(25): 5107-20.
  • Cherepanova O.A., Pidkovka N.A., Sarmento O.F., Yoshida T., Gan Q., Adiguzel E., Bendeck M.P., Berliner J., Leitinger N., Owens G.K. 2009. Oxidized Phospholipids Induce Type VIII Collagen Expression and Vascular Smooth Muscle Cell Migration. Circ Res 104: 609-618.
  • Cherepanova O.A., Pidkovka N., Leitinger N., Owens G. The oxidized phospholipid POVPC induces MMP3 expression and enhances migration of vascular smooth muscle cells 2008. FASEB J 22: 329.2.
  • Pidkovka, N.A., Cherepanova O.A., Yoshida T., Alexander M.R., Deaton R.A., Tomas J.A., Leitinger N., Owens G.K. 2007. Oxidized Phospholipids Induce Phenotypic Switching of Vascular Smooth Muscle Cells In Vivo and In Vitro. Circ Res 101: 792-801.

Anh Nguyen, PhD
Non-licensed Intermediate Clinical Research Coordinator

atn5w@virginia.edu


Angela Washington
Lab Specialist

amw7de@Virginia.edu


Amber Saenz
Mouse Colony Manager

ahs2t@Virginia.edu


Rupa Tripathi
Lab Manager

rnt4h@virginia.edu

Rupa has been with the Owens Lab for over sixteen years. She runs the cell culture core in the lab and helps with all cell culture experiments, including primary smooth muscle cell isolation, aortic explants, cell proliferation and migration assays. Rupa also manage the lab inventory and equipment, as well as making orders for supplies to the entire lab. She recently took over the lab manager responsibility at the end of June 2018.


Rebecca Deaton, PhD
Research Scientist

rad5x@Virginia.edu


Liming Yu, PhD
Research Associate

ly3h@virginia.edu


Santosh Karnewar, PhD
Research Associate

sk9cf@virginia.edu

I am Santosh Karnewar. I obtained my B.Sc. in Biotechnology, Zoology and Chemistry from NIZAM College (Autonomous) and MSc in Biochemistry from University College of Science (Osmania University) in India. I have completed my PhD with Dr. Srigiridhar Kotamraju at Chemical Biology department, CSIR-Indian Institute of Chemical Technology (AcSIR) in June 2017. My PhD thesis was on “Studies on the role of AMPK-mediated pathways during atherosclerosis and preventive strategies”.

As a graduate student I have studied age-associated atherosclerosis in Apo E-/- mice and now I joined the Dr.Owens lab in September 2017. In my project we will test the hypothesis that “Age associated changes in Smooth Muscle Cell and/or Endothelial Cell function negatively impact late stage atherosclerotic lesion pathogenesis by using unique mouse models. We will also study the skin wound healing and vascular injury-repair in young and aged SMC lineage tracing non-ApoE KO WT and SMC Oct4 and/or Klf4 KO mice. Klf4 and Oct4 KO models are unique models and Owens group reported in recent publications, Laura S Shankman (2015- nature medicine) and Olga A Cherepanova (2016- nature medicine).

Selected Publications:

  • Katta S, Karnewar S, Panuganti D, Jerald MK, Sastry B.K, Kotamraju S. Mitochondria-targeted esculetin inhibits PAI-1 levels by modulating STAT3 activation and miR-19b via SIRT3: Role in acute coronary artery syndrome. J Cell Physiol. 2017; 9999:1–12.
  • Karnewar S, Vasamsetti SB, Gopoju R, Kanugula AK, Ganji SK, Sripadi P, Rangaraj N, Tupperwar N, JM Kumar, Kotamraju S: Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis. Scientific Reports. 2016; 6, 24108.
  • Vasamsetti SB, Karnewar S, Gopoju R, Gollavilli PN, Narra SR, JM Kumar, Kotamraju S: Resveratrol attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of intracellular GSH homeostasis: Relevance in atherosclerosis. FRBM 05/2016; 96.
  • Vasamsetti SB, Karnewar S, Kanugula AK, Raj AT, Kumar JM, Kotamraju S: Metformin inhibits monocyte-to-macrophage differentiation via AMPK mediated inhibition of STAT3 activation: Potential role in atherosclerosis. Diabetes. 2015 Jun; 64(6):2028-41.
  • Khatua TN, Padiya R, Karnewar S, Kuncha M, Agawane SB, Kotamraju S, Banerjee SK: Garlic provides protection to mice heart against isoproterenol-induced oxidative damage: Role of nitric oxide. Nitric Oxide 03/2012; 27(1):9-17.

Patents:

  • Kotamraju S, Karnewar S, Vasamsetti SB, Togapur PK, BVS Reddy, JM Kumar: An Antioxidant compound having anti atherosclerotic effect and preparation thereof. Ref. No: 15/047,842-USA 2-19-2016, GB-L&S Ref No. : PD019488GB-CON,: 478/DEL-19 -FEB-2015-INDIA, Year: 02/2015.
  • Raji Reddy, Ch.; Srigiridhar, K.; Santosh, K.; Babu, B. N.; Nagasenkar, A.; Anuradha, S. C5, C6 Substituted and/or fused oxindoles as anti-cancer agents and process for preparation thereof (File no. 201611037409, 2016).
  • SP Singh, Thumuganti G, Kotamraju S, Karnewar S. A patent has been filed entitled “Novel Borondipyrromethene Fluorochromes Tailored with Phenoxymethylpyridine and Application as for” 0067NF2017.

Gamze Bulut, PhD
Postdoctoral Fellow

gbb8b@virginia.edu

My name is Gamze Bulut. I obtained my B.Sc. in Molecular Biology and Genetics from Bilkent University in Turkey. Then I moved to USA in 2008 to do my Ph.D. at UT Southwestern Medical Center at Dallas, TX. I worked in Dr. Lily Huang's laboratory in Department of Cell Biology. My Ph.D. thesis was on "Ubiquitination of Erythropoietin Receptor (EpoR) and p85 in ligand induced EpoR down regulation", which involved studying cell biology and protein modifications. Then we moved to Richmond, VA for my husband's new job at VCU Computer Science.

I started my postdoctoral training in Dr. Charles Chalfant's laboratory in October 2015 investigating the alternative splicing of Caspase 9 by the RNA trans factor hnRNP L to produce a gain of function variant called Caspase 9b. My brief postdoc in the Chalfant lab involved characterization of a transgenic mouse line expressing human Caspase 9b in the lung, cooperation with oncogenes in lung cancer formation, recombinant protein purification using baculovirus system and RNA protein binding through EMSA assays.

Dr. Chalfant and his lab moved to Florida and I have joined Dr. Gary Owens's laboratory at the Cardiovascular Research Center at University of Virginia in September 2017. Owens lab studies smooth muscle cell (SMC) phenotype switching using unique lineage tracing mouse models. My project is about diet induced obesity and how microvasculature is affected within the pathological adipose depots. Specifically, we will investigate the phenotypic switching of SMC upon diet induced obesity and the role of pluripotency factor Klf4 in these changes using different lineage tracing models. We will also generate new mouse models to investigate the effect of gender on atherosclerosis.


Vlad Serbulea, PhD
Postdoctoral Fellow

vs9ck@virginia.edu


Alexandra Newman
Graduate Student

aan6gj@virginia.edu

I am a fourth year graduate student in the Biochemistry and Molecular Genetics department, doing research in the Owens lab. I came to UVA from New York, where I worked in the Division of Cardiology at NYU Medical Center after graduating from Rensselaer Polytechnic Institute in Troy, NY in 2010. My previous research was in Alzheimer's disease.

The main project I am working on is: "PDGF Beta Receptor Dependent Smooth Muscle Cell Phenotypic Switching in Atherosclerotic Plaque Stabilization". PDGFs, the ligands of the PDGFRs are major mitogens of smooth muscle cells, inducing their migration and proliferation. It is widely thought that inhibiting PDGFBR will ameliorate atherosclerosis by leading to a decrease in smooth muscle cells within the lesion, and therefore reduced lesion size. This idea is based in part on the fact that antagonism of PDGFBR reduces SMC mediated lumen obstruction that occurs after stent placement. However, SMC are thought to be the protective cell types within the lesion, leading to stabilization and reduced rupture. Blocking their migration and proliferation may actually weaken the atherosclerotic lesion, leading to plaque rupture and thrombosis. Instead, we want to apply the opposite logic, i.e. increase PDGFBR signaling in the lesion in order to augment the protective SMC layer. This could eventually lead to exciting novel therapeutics.


Ryan Haskins
Graduate Student

rmh5bc@virginia.edu

I graduated from Case Western Reserve University in 2012 with a B.S. in Biology. Upon graduation, I joined the University of Virginia BIMS program to pursue my PhD in biological sciences. I have since joined the Pathology department and advanced to PhD candidacy in 2014. My main scientific interests are related to cell plasticity. I'm particularly interested in phenotypically plastic cells, such as smooth muscle cells (SMC), and their applications to regenerative medicine.

My first project title is "Elucidating the roles of Klf4 and Oct4 in smooth muscle cell phenotypic switching during atherosclerosis". Utilizing an ApoE KO model of mouse atherosclerosis, as well as SMC specific knockouts of Klf4 and Oct4, I will be investigating the role of these pluripotency factors specifically in smooth muscle cells in the pathogenesis of atherosclerosis. Flow cytometry and high resolution confocal microscopy are being utilized to assess the various phenotypes SMC acquire during atherosclerosis, including macrophage and MSC like states. I have also performed RNA Seq and ChIP Seq experiments on sections of aorta/brachiocephalic artery/carotid arteries in Klf4 and Oct4 knockout and wild type animals to identify in vivo targets of these genes, specifically in SMCs in late stage atherosclerosis.

My second project in the lab investigates SMC plasticity in various models of injury repair. Our hypothesis is that SMC may act as a local source of MSCs throughout the body. Experimentally, we have seen that SMCs contribute to the myofibroblast population in the infarct zone post infarction. Other models that will be, or have been, used to investigate the limits of SMC plasticity include a dermal skin wound model, partial hepatectomy, and a mouse digit tip amputation model.


Gabriel Falcao Alencar
Graduate Student

gf8kz@virginia.edu

My name is Gabriel Falcao Alencar and I am currently a second year at the Biochemistry and Molecular Genetics program at UVa. I did both my undergrad (Biological Sciences) and my Master's degree (Medical Sciences - Human Genetics) at the University of Brasilia - Brazil, where I am from. After finishing my Master's degree, I came to the USA to work at the Hereditary Genomics Lab at the University of Kentucky under Dr. James Hartsfield. There, my research was mainly identifying genetic loci involved in the development of orthodontics problems, such as mandibular prognathism (theme of my Master's thesis), as well as familial non-medullary cancer, ovarian cancer, and aging.

My main project in the Owens' Lab is: "KLF4 dependent maintenance of microvascular integrity". It is well established that the transcription factor KLF4 is not expressed in smooth muscle cells (SMC) in large conduit arteries in healthy mature animals. However, it appears to be expressed in SMC and pericytes (SMC-P) of the microvasculature and have a functional, and potentially physiological, role in the correct maintenance of perivascular coverage. It is also important to note that alterations within the microvasculature play a key role in the development of cardiovascular disease and complications of diabetes. Therefore, I am trying to identify how KLF4 recruitment, maintenance and/or survival of the SMC-P within the microvasculature in a healthy animal model.

I am also interested in computational biology and using high-throughput sequence data to investigate the role of histone markers and transcription factors in the differentiation/de-differentiation of SMC-P, both in injury models as well as in vitro models, and in disease. To date, we have generated and analyzed ChIP-seq (chromatin imunnoprecipitation sequence) datasets for KLF4 in an atherosclerosis setting and in mesentery of healthy animals, as well as RNA-seq of OCT4 and KLF4 KO in different models.


Daniel Hess
MD/PhD student

dlh4dc@virginia.edu

I grew up in Augusta, GA and attended the University of Georgia (UGA) where I studied biology. While at UGA, I worked in the lab of Steve Dalton, PhD studying the differentiation of hESCs and iPSCs to mesodermal lineages. I also spent three summers in the lab of William (Dave Hill), PhD at Georgia Regents University investigating how modulation of autophagy affects ischemic brain injury.

I began the MD/PhD (NIH MST) program at UVa in July 2012 and joined the Owens lab in April 2014. I am currently investigating the role of the stem cell pluripotency factor Oct4 in perivascular cell-mediated vascular repair and remodeling following ischemic injury.



Richard (Ricky) Baylis
MD/PhD student

rab5uh@virginia.edu

I received a BS in Biomedical Engineering at the Ohio State University. I performed the majority of my undergraduate research in Dr. Palumbo's lab at Cincinnati Children's Hospital looking at how the coagulation cascade impacts colitis associated colon cancer. I have just completed the first two years of medical school and will transition to the lab this Spring to start my graduate training.


Katherine (Katie) Owsiany
MD/PhD student

ko8xh@virginia.edu


Lillian Waller
MD/PhD student

lkw2re@virginia.edu