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.

Paul Bray, MD

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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:

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  • 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

Publications

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

Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression

Transfection of human platelets with short interfering RNA

MicroRNAs in platelet production and activation

Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity

Members

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Paul Bray, MD
Professor

kong

Xiango Kong, MD
Research Associate

lindsay

Corey Lindsay, PhD
Research Assistant

bhatlekar

Seema Bhatlekar, PhD
Postdoctoral Fellow

whitley

Michael Whitley
Graduate Student

ma

Lin Ma
Research Technician

Past Members

trueuel-montoya

Raul Trueuel-Montoya

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.

  • The DLK1-DIO3 locus in an imprinted region of the genome containing 54 maternally-expressed miRNAs. Among hematopoietic cells, these miRNAs are platelet specific. We have generated data that expression of these miRNAs increases during megakaryopoiesis and that early overexpression inhibits megakaryopoiesis. We are investigating the role of these miRNAs in megakaryocyte development.

  • 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

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

Mechanisms of constitutive NF-κB activation in human prostate cancer cells

Members

Johnny Yu
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

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)

Thrombopoietin following transfusion of platelets in preterm neonates

Members

mckenzie

Steven E. McKenzie, MD PhD

abraham

Shaji Abraham, PhD

zhou

Yuhang Zhou

Past Members

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

Brendan Bachman, M.S.

Randall Derstine, MS

Vilas Desai, PhD

Kalyan Golla, PhD

Meghna U. Naik, MSc

Pravin Patel, BS

Cardeza Seminars

All Seminars in Cardeza Library (Curtis Building Room 903) at 12:00 pm unless otherwise noted.

2015

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

2014

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)