The Cardeza Center pursues a broad range of basic research that can be divided into three focus areas: basic research, clinical/translational and core laboratories. We also host a seminar series during the academic year.
Leonard Edelstein, PhD
Dr. Edelstein’s laboratory studies gene expression in megakaryocytes and platelets and their role in cardiovascular disease and thrombopoiesis. Current research includes:
Activated platelets release microparticles (MPs) which contain RNA and protein. These MPs have been shown to deliver miRNAs to endothelial cells in culture and alter the level of RNAs in these cells. We are studying this effect in a flow chamber in which the endothelial cells are cultured under shear stress and then analyzing the effect on genes regulated by inflammation or shear stress, two processes important to atherosclerotic plaque formation.
Genome wide association studies have identified ~50 loci in the human genome associated with heart attacks. However, neither the genetic variant responsible for the increased risk nor the cell type in which it functions has been identified. We are developing methods to identify which locus-linked genes are functional in platelets and the effect the common variants have on their expression and function.
Arterial hypertension is associated with thrombotic events due to platelet activation. The exact mechanism by which hypertensive platelets become more sensitive to agonist stimulation is unknown. We have collected platelet miRNA from healthy and pre-hypertensive subjects and found association between miRNA level and blood pressure. We will use this data to identify differentially expressed genes responsible for the increased function in platelets.
Leonard Edelstein, PhD
Research Assistant Professor
Xiango Kong, MD
Namrata Madan, PhD
Arie Horowitz, D.Sc.
My laboratory conducts basic research in vascular biology. Our objective is to understand how blood vessels regulate the permeability of their walls. Specifically, we study how the junctions between adjacent endothelial cells on the lumen of vessels are maintained, and how they respond to external stimuli, such as vascular endothelial growth factor. We pursue these questions by probing intracellular signaling pathways and protein complexes that determine the behavior of the junctions. We use cell culture and genetically modified mouse models in combination with advanced optical imaging techniques.
In addition to my membership in the Cardeza Center, I am an adjunct faculty in Cancer Biology, and a member of the Genetics, Genomics and Cancer Biology graduate program, and of the Sidney Kimmel Cancer Center in the Extracellular Matrix and Metastasis program.
Our three major ongoing projects are:
1. Regulation of cell junction dynamics by membrane traffic. We found that the GTPase Rab13, which recycles tight junction proteins, facilitates the translocation of RhoA and its guanine exchange factor PLEKHG5/Syx from cell junctions to the cell leading edge (Wu et al., 2011). This implicates Rab13 in cell migration, a previously unknown function of this protein. We are investigating the in vivo function of Rab13 using a new mouse model with an endothelial cell-specific deletion of rab13. We previously found that global deletion of rab13 is embryonic lethal. In collaboration with the synthetic chemistry lab of Dr. Katarzyna Błażewska at Lodz University of Technology, we are screening small molecule inhibitors of vascular development in the zebrafish, in order to identify compounds that may inhibit angiogenesis.
2. Large-scale identification of genes involved in mediating the effects of VEGF on endothelial cell junctions. We are leveraging CRISPR-dCas9 gRNA inhibitory and activating libraries in order to either silence or activate genes that code for proteins that are components of specific pathways. Our current focus is on VEGF, but we will pursue additional cell-junction modifying pathways, e.g. angiopoietin. In order to generate sufficient coverage of the gRNA libraries, which code for all the annotated human genes, we miniaturized the permeability assay to 100-200 mm microcarrier beads. The beads are permeable and take up fluorescent probes once the confluent cell monolayer that covers them is exposed to VEGF. The resulting light signal facilitates the sorting of the beads to separate those where junction response to VEGF was inhibited. In collaboration with Dr. Eric Londin from the Computational Medicine Center of Thomas Jefferson University, we will identify genes that are required for the effect of VEGF on cell junctions.
3. The basis of signal specificity in endothelial cell junctions. VEGF and angiopoietin-1 are essential for blood vessel viability and integrity, but they have opposite effects on endothelial cell junctions. While the former triggers junction disassembly, the latter stabilizes them. Our previous study (Ngok et al., 2012) indicated that the localization of the RhoA guanine exchange factor Syx can explain in part the opposite effects of VEGF and Ang1 on cell junctions. Syx is displaced from cell junctions by VEGF, whereas Ang1 retains Syx at the junctions. Numerous junction transmembrane and cytoplasmic proteins are scaffolded by the large adaptor protein MPDZ. Therefore, we employ MPDZ as a convenient tool for determining how different agonists generate different. We identified new binding partners of MPDZ that may link its function to membrane trafficking, and are currently analyzing the molecular basis of MPDZ’s function. In parallel, we are phenotyping a new mpdz loss-of-function mouse model, to test the in vivo function of MPDZ. The preliminary phenotyping data suggest that mpdz-/- mice suffer from several major anatomic and functional effects, including loss of hearing and heart hypertrophy.
Erratum: Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles (Proceedings of the National Academy of Sciences of the United States of America (August 22, 2006) 103, 34 (12735-12740) DOI: 10.1073/pnas.0605317103)
Arie Horowitz, DSc
Junning Yang, PhD
Claire Simonneau, PhD
Ioana Stefanescu, B.Sc.
Steven McKenzie, MD PhD
Dr. McKenzie is a Hematology physician-scientist with clinical expertise in adult and pediatric non-malignant hematologic disorders and a scientific expertise in translational research. He works in the Cardeza Hemophilia and Thrombosis Center and also in the Hereditary Anemias Center. He is a member of the Sidney Kimmel Cancer Center (SKCC), in the Molecular Biology and Genetics Program. He is a member of two Graduate Programs:
Genetics, Genomics and Cancer Biology
Immunology and Microbial Pathogenesis
He is a physician mentor for Thomas Jefferson University MD/PhD program.
Dr. McKenzie directs two major laboratory research projects. The first project has a focus on immune-mediated thrombocytopenia and thrombosis syndromes (see McKenzie and Sachais, Current Opinion in Hematology, September 2014). This work led to the first and only mouse model of heparin-induced thrombocytopenia and thrombosis (HIT). The current work explores Novel Therapeutics in HIT, in an NIH-supported Program Project grant with Drs. Poncz and Rauova at Children’s Hospital of Philadelphia, Drs. Cines, Sachais and Cuker at University of Pennsylvania, and Dr. Arepally at Duke. In another subproject, Dr. McKenzie is co-funded on an NIH R01 with Dr. Bergmeier at UNC Chapel Hill and Dr. Woulfe at University of Delaware to explore platelet signaling mechanisms.
The second major McKenzie lab project focuses on the Genomics and Molecular Genetics of inter-individual variation in human platelet activation via FcgammaRIIa. This molecule has dual functions, as a receptor for IgG immune complexes and as a transmembrane adapter in integrin “outside-in” signaling. In collaboration with Dr. Paul Bray, who led the PRAX1 study, our team has identified differentially expressed mRNAs and miRNAs as well as genomic variants that regulate platelet reactivity. Team members of our longstanding Platelet Interest Group are Drs. Bray, McKenzie, Holinstat, Edelstein and Naik at Thomas Jefferson University, Drs. Rigoutsos and Londin at Thomas Jefferson University Computational Medicine Center, Dr. Fortina of SKCC Genomics, Drs. Shaw and Simon at Baylor, and Dr. Kunapuli at Temple. Dr. McKenzie is also co-funded, with Dr. Holinstat as PI, on work that involves 12-LOX and diabetes vascular biology. Our foci in the McKenzie lab moving forward are novel molecular genetic pathways for determination of receptor levels, protein tyrosine phosphatase activity and oligo-ubiquitylation in platelet FcgammaRIIa functions.
Identification of a developmental gene expression signature, including hox genes, for the normal human colonic crypt stem cell niche: Overexpression of the signature parallels stem cell overpopulation during colon tumorigenesis
Steven E. McKenzie, MD PhD
Shaji Abraham, PhD
Ulhas P. Naik, PhD
The Naik laboratory is focused on developing therapeutic strategies to interrupt the progress of cardiovascular disease and cancer. In this regard, the team has identified several novel gene products that play key regulatory roles in the progression of these diseases. Using cell and molecular biological approaches, the team has characterized the potential role of calcium- and integrin-binding protein family and junctional adhesion molecule family members in physiological and pathological settings. Cutting edge technologies, such as the yeast two-hybrid system, siRNA, transgenic mouse models, systems biology, nanotechnology and fluid dynamics modeling are routinely employed in the laboratory.
Some specific projects involve:
Positive and negative regulatory mechanisms of platelet activation during thrombosis
Mechanism of new blood vessel formation (angiogenesis) during ischemia and cancer
Mechanism of breast and prostate cancer cell metastasis
Use of nanotechnology to deliver drugs to specifically targeted sites
Fraunhofer-UD Research Grant
Ulhas P. Naik, PhD
Brendan Bachman, MS
Randall Derstine, MS
Kalyan Golla, PhD
Meghna U. Naik, MSc
Pravin Patel, BS
September 7 – Peisong Ma, PhD, (Penn), Curtis 218
September 21 – Ramani Ramchandran, PhD, (Medical College of Wisconsin), Curtis 218
September 28 – Rosario Scalia, MD, PhD, (Temple), Curtis 218
October 12 – Satoru Eguchi, MD, PhD, (Temple) Curtis 218
October 26 – Kellie Machalus, PhD, (Harvard), Curtis 218
November 2 – Martha Sola-Visner, MD, (Harvard), Curtis 218
November 16 – Alexander M. Mazo, PhD, (Jefferson), Curtis 218
November 30 – Stephen Vatner, MD, (Rutgers), Curtis 218
December 21 – Colin Greineder, MD, PhD, (Penn), Curtis 218
January 4 – Yi Fan (Penn)
January 25 – Adam Cuker, MD, (Penn), TBD
February 1 – Bruno Calabretta, MD, PhD, (Jefferson), TBD
February 22 – Jianxin Sun, PhD, (Jefferson), TBD
March 1 – James Keen, PhD, (Jefferson), TBD
March 22 – Jason M. Butler, PhD, (Cornell), TBD
April 12 – Peter Newman, PhD, (Wisconsin Blood Center), TBD
April 26 – Suresh Joseph, PhD, (Jefferson), TBD
May 10 – Jean Baum, PhD, (Rutgers)
May 24 – TBD
All Seminars in Jefferson Alumni Hall 307 at 12:00 pm unless otherwise noted.
September 9 - Gerd A. Blobel, MD, PhD (CHOP)
October 14- Vinod Vijayan, Ph.D. (Baylor College of Medicine)
November 11 - Fabio Recchia, MD, PhD (Temple)
December 2 - Bing-Hua Jiang, PhD (Jefferson)
December 16 - Andrew E. Aplin, PhD (Jefferson)
January 6 - Daniel J. Rader, MD (UPenn)
January 20 – Gyorgy Hajnoczky, MD, PhD (Jefferson)
February 10 - Lawrence E. Goldfinger, PhD (Temple)
February 24 - Khadija Rafiq, PhD (Jefferson)
March 2 - Paul J Gadue, PhD (CHOP)
March 16 - Ross S. Summer, MD (Jefferson)
April 13 - Wei Tong, PhD (CHOP)
April 27 - Philip B.Wedegaertner, PhD (Jefferson)
May 11 - Patrick Provost (Centre Hospitalier de l'Université Laval (CHUL))
2014 - 2015
September 3 – Caleb Kallen (Thomas Jefferson University)
September 17 – Shey-Shing Sheu (Thomas Jefferson University)
October 1 – Deepak Deshpande (Thomas Jefferson University)
October 15 – Domenico Pratico (Temple University)
October 29 – John Semple (University of Toronto; St. Michael’s Hospital)
November 12 – John Weisel (University of Pennsylvania)
January 28 – Athan Kuliopulos (Tufts University)
February 11 – Rajanikanth Vadigepalli (Thomas Jefferson University)
February 25 – Khadija Rafiq (Thomas Jefferson University)
March 11 – Robert Flaumenhaft (Harvard University)
March 25 – Jean Pierre Issa (Temple University)
April 8 – Shawn Jobe (Milwaukee Blood Research Institute)
April 22 – Jerry Nadler (EVMS, Chair of Medicine)
May 13 – Ian Blair (University of Pennsylvania)
May 27 – TBA