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.
Paul Bray, MD
Dr. Bray’s laboratory studies the role of platelets in cardiovascular disease and disorders of bleeding and excessive blood clotting. He identifies and characterizes novel variations in platelet genes and in platelet gene expression that affect both clinical and platelet phenotypes. His laboratory utilizes genomic and transcriptomic approaches, and molecular and cell biology approaches to address these important areas of research. He is a clinician-scientist who has been continuously funded by the National Institutes of Health from 1986 to the present. He is a member of the Genomics and Cancer Biology graduate program. Current areas of investigation include:
Studies on demographic effects on platelet function and thrombosis
Studies on microRNA function in human megakaryocytes
Testing for interactions between genetic variations and medications for clinical outcomes of myocardial infarction, stroke or bleeding
Testing for interactions between genetic variations and medications for platelet functional responses
Visit Plateletomics.com for more information.
Paul Bray, MD
Xiango Kong, MD
Seema Bhatlekar, PhD
Corey Lindsay, PhD
Raul Teruel-Montoya, PhD
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
Namrata Madan, PhD
Arie Horowitz, D.Sc.
The objective of our laboratory is to understand how blood vessels form at the basic level, and to exploit this information for therapeutic purposes, including the suppression of tumor growth, and, conversely, the restoration of blood flow in tissues where it has been reduced as a result of diabetes or heart attack. To gain insight into these processes we study how the movement and the junctions of endothelial cells in angiogenesis are coordinated to maintain vessel integrity. We use in vivo mouse models and in vitro cell biological approaches frequently involving advanced optical imaging techniques.
Ongoing studies include:
1. The regulation of cell junction dynamics by membrane traffic. We found that the GTPase Rab13 facilitates the repurposing of RhoA and its guanine exchange factor Syx from cell junctions to cell migration. We are investigating the function of Rab13 in the vasculature using a new mouse model with an endothelial cell specific Rab13 loss of function.
2. The molecular mechanism that confers the opposing effects of VEGF and angiopoietin-1 on endothelial cell junctions. We found that the localization of the RhoA guanine exchange factor Syx alternates between the cytoplasm and the cell junctions in response to VEGF and angiopoietin-1, respectively. We are studying the alterations in the composition of the protein complex that regulates Syx in response to each factor.
3. The regulation of focal adhesion dynamics by VEGF. We identified novel binding partners to the cytoplasmic tail of the VEGF coreceptor neuropilin-1. These findings implicate the receptor in regulating the rate of focal adhesion turnover and hence, in cell migration. We are addressing the still unknown molecular mechanism that couples neuropilin-1 to focal adhesions.
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, D.Sc
Junning Yang, PhD
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
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