Thomas Jefferson University
Sidney Kimmel Medical College
Department of Medicine

Research Activity

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

bray01

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:

bray02
  • Studies on demographic effects on platelet function and thrombosis

  • Studies on microRNA function in human megakaryocytes

  • Pharmacogenetic studies:

    • 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.

Protocols

Leukocyte Depleted Platelets (DOC)

Publications

Protease receptor antagonism to target blood platelet therapies

Anti-miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

Genome-wide association study of platelet aggregation in African Americans

Platelet Disorders (Inherited and Acquired)

Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

MicroRNA expression differences in human hematopoietic cell lineages enable regulated transgene expression

Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics

The human platelet: Strong transcriptome correlations among individuals associate weakly with the platelet proteome

PDK1 selectively phosphorylates Thr(308) on Akt and contributes to human platelet functional responses

Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c

Dengue platelets meet sir arthur conan doyle

Platelet Genomics

Erosive Arthritis and Hepatic Granuloma Formation Induced by Peptidoglycan Polysaccharide in Rats Is Aggravated by Prasugrel Treatment

MicroRNAs in platelet production and activation

The complex transcriptional landscape of the anucleate human platelet

Small RNAs as potential platelet therapeutics

Fractalkine is expressed in early and advanced atherosclerotic lesions and supports monocyte recruitment via CX3CR1

Human genome-wide association and mouse knockout approaches identify platelet supervillin as an inhibitor of thrombus formation under shear stress

Human genome-wide association and mouse knockout approaches identify platelet supervillin as an inhibitor of thrombus formation under shear stress

Platelet biology and response to antiplatelet therapy in women: Implications for the development and use of antiplatelet pharmacotherapies for cardiovascular disease

Members

Paul Bray, MD

Paul Bray, MD
Professor

Xiango Kong, MD

Xiango Kong, MD
Research Associate

Ahmed Chahdi, PhD
Research Associate

Seema Bhatlekar, PhD

Seema Bhatlekar, PhD
Postdoctoral Fellow

Seema Bhatlekar, PhD

Indranil Basak, PhD
Postdoctoral Fellow

Michael Whitley

Michael Whitley
Graduate Student

Lin Ma

Lin Ma
Research Technician

Past Members

Corey Lindsay, PhD

Corey Lindsay, PhD
Research Assistant

Raul Teruel-Montoya, PhD

Raul Teruel-Montoya, PhD
Postdoctoral Fellow

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.

Publications

Anti-miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

MicroRNA expression differences in human hematopoietic cell lineages enable regulated transgene expression

Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics

The human platelet: Strong transcriptome correlations among individuals associate weakly with the platelet proteome

Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis

Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c

MicroRNAs in platelet production and activation

The complex transcriptional landscape of the anucleate human platelet

Small RNAs as potential platelet therapeutics

Human genome-wide association and mouse knockout approaches identify platelet supervillin as an inhibitor of thrombus formation under shear stress

Human genome-wide association and mouse knockout approaches identify platelet supervillin as an inhibitor of thrombus formation under shear stress

High-throughput screening uncovers a compound that activates latent HIV-1 and acts cooperatively with a histone deacetylase (HDAC) inhibitor

MicroRNAs in platelet production and activation

Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity

Short communication: Activation of latent HIV type 1 gene expression by suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor approved for use to treat cutaneous T cell lymphoma

The SCAN domain family of zinc finger transcription factors

Chromatin Modification and the Endothelial-specific activation of the E-selectin gene

Nuclear Factor κB-Dependent Activation of the Antiapoptotic bfl-1 Gene by the Epstein-Barr Virus Latent Membrane Protein 1 and Activated CD40 Receptor

NF-κB-dependent assembly of an enhanceosome-like complex on the promoter region of apoptosis inhibitor Bfl-1/A1

Members

Leonard Edelstein, PhD

Leonard Edelstein, PhD
Research Assistant Professor

Namrata Madan, PhD

Namrata Madan, PhD
Postdoctoral Fellow

Johnny Yu

Johnny Yu
Research Technician

Arie Horowitz, D.Sc.

file

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.

Publications

The cytoplasmic domain of neuropilin-1 regulates focal adhesion turnover

VEGF and angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx

Stimulus-dependent phosphorylation of profilin-1 in angiogenesis

Regulation of VEGF signaling by membrane traffic

Rab13-dependent trafficking of RhoA is required for directional migration and angiogenesis

Erratum: Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways (Circulation Research (2008) 103 (e71-e79))

Imaging of growth factor-augmented angiogenesis after myocardial infarction: glimmers of a spatiotemporal pattern?

Cleavage of syndecan-4 by ADAMTS1 provokes defects in adhesion

Branching morphogenesis

The Amot/Patj/Syx signaling complex spatially controls RhoA GTPase activity in migrating endothelial cells

Branching morphogenesis

Syx, a rhoA guanine exchange factor, is essential for angiogenesis in vivo

Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways

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)

Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles

Selective Regulation of Arterial Branching Morphogenesis by Synectin

A PDZ-binding motif as a critical determinant of Rho guanine exchange factor function and cell phenotype

Protein kinase C (PKC) δ regulates PKCα activity in a syndecan-4-dependent manner

Fibroblast growth factor-specific modulation of cellular response by syndecan-4

Syndecan-4-mediated signalling

Members

Arie Horowitz, D.Sc

Arie Horowitz, D.Sc
Associate Professor

Junning Yang, PhD

Junning Yang, PhD
Research Associate

Claire Simonneau, PhD
Postdoctoral Fellow

Junning Yang, PhD

Ioana Stefanescu, B.Sc.
Research Technician

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.

Publications

Anti-miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- And tissue-specific microRNAs

Platelet 12-LOX is essential for FcγRIIa-mediated platelet activation

MicroRNA expression differences in human hematopoietic cell lineages enable regulated transgene expression

Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics

The human platelet: Strong transcriptome correlations among individuals associate weakly with the platelet proteome

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

CalDAG-GEFI deficiency protects mice from FcγRIIa-mediated thrombotic thrombocytopenia induced by CD40L and β2GPI immune complexes

Advances in the pathophysiology and treatment of heparin-induced thrombocytopenia

Tyrosine phosphorylation on spleen tyrosine kinase (Syk) is differentially regulated in human and murine platelets by protein kinase C isoforms

MicroRNAs in platelet production and activation

Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo

The complex transcriptional landscape of the anucleate human platelet

Monocytes in HIT: An evolving story

CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia

Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa)

PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model

Amelioration of murine immune thrombocytopenia by CD44 antibodies: A potential therapy for ITP?

Dominant expression of the inhibitory FcγRIIB prevents antigen presentation by murine plasmacytoid dendritic cells

The clot thickens (or not)

Members

Steven E. McKenzie, MD PhD

Steven E. McKenzie, MD PhD

Shaji Abraham, PhD

Shaji Abraham, PhD

Yuhang Zhou

Yuhang Zhou

Past Members

Pierette Andre

Pierette Andre

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

Current Projects

  • 2P20 RR015588-10

  • 1R01 HL113118-02

  • 1R01 HL119374-01

  • AHA Grant-in-Aid

  • Fraunhofer-UD Research Grant

Publications

Bacteria exploit platelets

Junctional adhesion molecule-A suppresses platelet integrin αIIbβ3 signaling by recruiting Csk to the integrin-c-Src complex

High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor

Junctional Adhesion Molecule-A Regulates Vascular Endothelial Growth Factor Receptor-2 Signaling-Dependent Mouse Corneal Wound Healing

Fucoidan is a novel platelet agonist for the C-type lectin-like receptor 2 (CLEC-2)

Effects of JAM-A deficiency or blocking antibodies on neutrophil migration and lung injury in a murine model of ALI

A spatial model for integrin clustering as a result of feedback between integrin activation and integrin binding

CASK interacts with PMCA4b and JAM-A on the mouse sperm flagellum to regulate Ca2+ homeostasis and motility

Pericyte-endothelial cell interaction: A survival mechanism for the tumor vasculature

JAM-A protects from thrombosis by suppressing integrin α IIbβ 3-dependent outside-in signaling in platelets

Calcium- and integrin-binding protein 1 regulates megakaryocyte ploidy, adhesion, and migration

Contra-regulation of calcium- and integrin-binding protein 1-induced cell migration on fibronectin by PAK1 and MAP kinase signaling

Efficient implementation of the proper outlet flow conditions in blood flow simulations through asymmetric arterial bifurcations

Probabilistic modeling and analysis of the effects of extra-cellular matrix density on the sizes, shapes, and locations of integrin clusters in adherent cells

An impedance model for blood flow in the human arterial system. Part I: Model development and MATLAB implementation

Application of 1D blood flow models of the human arterial network to differential pressure predictions

Calcium-dependent inhibition of polo-like kinase 3 activity by CIB1 in breast cancer cells

Calcium- and integrin-binding protein 1 regulates endomitosis and its interaction with polo-like kinase 3 is enhanced in endomitotic dami cells

Calcium- and integrin-binding protein 1 regulates microtubule organization and centrosome segregation through polo like kinase 3 during cell cycle progression

Integrin αIIbβ3: A novel effector of Gα13

Members

Ulhas P. Naik, PhD

Ulhas P. Naik, PhD

Brendan Bachman, MS

Brendan Bachman, MS

Randall Derstine, MS

Randall Derstine, MS

Kalyan Golla, PhD

Kalyan Golla, PhD

Meghna U. Naik, MSc

Meghna U. Naik, MSc

Pravin Patel, BS

Cardeza Seminars

2015-2016

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