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.

Lawrence Goldfinger, PhD

We are seeking to understand the molecular cell biology regulating how circulating blood platelets contribute to hemostasis and thrombosis, and to apply this understanding to modulate platelet function in various contexts. Our research program spans molecular studies of control of platelet gene expression, the cell biological outcomes of this regulation, physiological studies of platelet function, and development of tools for pre-clinical applications in health and disease.


Current Research Projects



Platelet microRNAs as modulators of hemostasis and thrombosis

Hemostasis (prevention of blood leak after vascular injury by formation of a clot) and thrombosis (clot formation generally not in response to injury, which can cause pathological complications) are considered the primary functions of platelets, and platelets require many genes to carry out these functions. In addition to those genes, platelets are enriched in small non-coding RNAs known as microRNAs (miRNAs) that are generally understood to function to dampen the expression levels of protein-coding genes, and thereby suppress gene activity. We have found that miRNAs are important regulators of platelet function. We are seeking to understand how miRNAs regulate platelet function in hemostasis and thrombosis, to identify the specific miRNAs and gene targets involved, and to develop strategies to manipulate miRNA function and modulate platelet reactivity to support hemostasis or suppress thrombotic potential.


Molecular control of mRNA translation in platelets

Platelets are anucleate cell fragments that circulate in blood for 7-10 days. Hence, platelets lack genomic DNA but they do contain protein-coding message RNAs (mRNAs), un-spliced pre-mRNAs and mRNA splicing machinery, as well as all the necessary molecular and cellular components to support translation of mRNA into protein, and to degrade existing proteins. Platelet reactivity, hemostatic capacity and thrombotic potential vary widely in humans, and we are investigating how control of protein translation contributes to this variation. Although mRNA translation in platelets (despite an inability to generate new mRNAs) was recognized many years ago, very little remains known about how platelets translate new protein necessary for their ongoing metabolism and reactivity while in circulation. We are exploring the molecular signaling controlling mRNA translation in circulating platelets, including the roles of platelet miRNAs, and the cellular and physiological outcomes and effects. Based on these mechanistic studies, we are developing translational approaches to control platelet reactivity via miRNA manipulation and other approaches in multiple contexts.

Recent Publications

GRK6 regulates the hemostatic response to injury through its rate-limiting effects on GPCR signaling in platelets

High-efficiency unassisted transfection of platelets with naked double-stranded miRNAs modulates signal-activated translation and platelet function

Horizontal RNA transfer goes deep: platelet consumption and microRNA utilization by vascular smooth muscle cells

ELMO1 deficiency enhances platelet function

Concepts and advances in cancer therapeutic vulnerabilities in RAS membrane targeting

GPVI inhibitor as antitumor gateway drug

TC21/RRas2 regulates glycoprotein VI–FcRγ-mediated platelet activation and thrombus stability

Defective RAB1B-related megakaryocytic ER-to-Golgi transport in RUNX1 haplodeficiency: Impact on von Willebrand factor

Platelet Microparticles and miRNA Transfer in Cancer Progression: Many Targets, Modes of Action, and Effects Across Cancer Stages

Transcription factor RUNX1 regulates platelet PCTP (phosphatidylcholine transfer protein): Implications for cardiovascular events differential effects of RUNX1 variants

Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth

Dysregulation of PLDN (pallidin) is a mechanism for platelet dense granule deficiency in RUNX1 haplodeficiency

Regulation of Ras signaling and function by plasma membrane microdomains

Inhibition of galectin-1 sensitizes hras-driven tumor growth to rapamycin treatment

Dicer1-mediated miRNA processing shapes the mRNA profile and function of murine platelets

The RLIP76 N-terminus binds ARNO to regulate PI 3-kinase, Arf6 and Rac signaling, cell spreading and migration

RLIP76 regulates Arf6-dependent cell spreading and migration by linking ARNO with activated R-Ras at recycling endosomes

RLIP76 regulates HIF-1 activity, VEGF expression and secretion in tumor cells, and secretome transactivation of endothelial cells

Three-dimensional reconstruction of neovasculature in solid tumors and basement membrane matrix using ex Vivo X-ray microcomputed tomography

Activation of PI3K and R-ras signaling promotes the extension of sensory axons on inhibitory chondroitin sulfate proteoglycans

RhoG protein regulates glycoprotein VI-Fc receptor γ-chain complex-mediated platelet activation and thrombus formation

Integrin Signaling

Emerging treatments in lung cancer - targeting the RLIP76 molecular transporter

RALBP1/RLIP76 depletion in mice suppresses tumor growth by inhibiting tumor neovascularization

Palmitoylation regulates vesicular trafficking of R-Ras to membrane ruffles and effects on ruffling and cell spreading

Current Lab Members

Peisong Ma, PhD

Dr. Ma’s laboratory is involved with investigating thrombosis and hemostasis, with a special emphasis on understanding GPCR (G-protein coupled receptor) and G-protein mediated platelet activation. Many antiplatelet drugs target GPCRs and G protein signaling pathways. Our current studies provide novel insights into the regulatory mechanisms that allow platelets to produce an optimal response to vascular injury. Using well-established vascular injury models, CRISRP-Cas9 genome-editing, and biochemical approaches, we have provided strong evidence that defects in GPCR and G-protein signaling pathways translate into in vivo phenotypes. The following is a brief summary of major ongoing projects in the lab.

Project 1: RGS-insensitive Gq (G188S) as probes of G protein functions

We have recently developed a mutant mouse line with a mutation (G188S) in the Gq subunit that renders the G protein resistant to interaction with RGS (regulator of G protein signaling) proteins as a class. In contrast to enhanced Gi2 signaling in Gi2(G184S) mutant platelets, we have observed decreased platelet activation in Gq(G188S) mutant mice, suggesting that the negative feedback mechanism of Gq regulation is different from that of Gi2. An ongoing study is to fully characterize the effect of G188S mutation on platelet function and thrombus formation.

Project 2: The signaling machinery that provides negative feedback regulation to G protein-dependent signaling during platelet activation

We have recently provided strong evidence that GPCR kinases (GRKs) are critical negative regulators during platelet activation. SNPs (single nucleotide polymorphisms) of GRKs are associated with the risk of stroke, hypertension, cardiac failure, and venous thromboembolism. Our goals are to investigate how GRKs regulate GPCRs and G proteins during platelet activation and thrombus formation, and to understand how dysfunctional regulation of GRKs may lead to thrombotic events and cardiovascular disease.

Project 3: The regulatory networks that regulate platelet activation downstream of G protein signaling using genome-wide screening

We have established that αIIbβ3 activation as a readout for genome-wide pooled CRISPR-Cas9 screen in primary megakaryocytes. We will identify novel positive regulators and negative regulators that control integrin activation in response to GPCR-coupled agonists.

Recent Publications

RGS10 and RGS18 differentially limit platelet activation, promote platelet production, and prolong platelet survival

The roles of GRKs in hemostasis and thrombosis

GRK6 regulates the hemostatic response to injury through its rate-limiting effects on GPCR signaling in platelets

High-efficiency unassisted transfection of platelets with naked double-stranded miRNAs modulates signal-activated translation and platelet function

RGS10 shapes the hemostatic response to injury through its differential effects on intracellular signaling by platelet agonists

A systems approach to the platelet signaling network and the hemostatic response to injury

Modulating platelet reactivity through control of RGS18 availability

Dissociation of SHP-1 from spinophilin during platelet activation exposes an inhibitory binding site for Protein Phosphatase-1 (PP1)

Applying the brakes to platelet activation

A newly identified complex of spinophilin and the tyrosine phosphatase, SHP-1, modulates platelet activation by regulating G protein-dependent signaling

Platelet signaling

Regulating thrombus growth and stability to achieve an optimal response to injury

Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin (Journal of Cell Biology (2006) 174, 7, (1097-1106))

RGS/Gi2α interactions modulate platelet accumulation and thrombus formation at sites of vascular injury

Focus on Molecules: Lacritin

Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin

Restricted epithelial proliferation by lacritin via PKCα-dependent NFAT and mTOR pathways

Characterization of the seabass pancreatic α-amylase gene and promoter

Hormonal influence on amylase gene expression during Seabass (Lates calcarifer) larval development

Erratum: Hormonal influence on amylase gene expression during Seabass (Lates calcarifer) larval development (General and Comparative Endocrinology (2004) 138 (14-19) DOI: 10.1016/j.ygcen.2004.04.007)

Ontogeny of α-amylase gene expression in sea bass larvae (Lates calcarifer)

Current Lab Members

Lin Ma

Peisong Ma, PhD
Assistant Professor

Lin Ma

Xi Chen
Postdoctoral Fellow

Lin Ma

Xuefei Zhao
Graduate Student

Lin Ma

Matthew Cooper
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.

Recent Publications

FcgRIIA expression accelerates nephritis and increases platelet activation in systemic lupus erythematosus

Apoptosis signal-regulating kinase 1 regulates immune-mediated thrombocytopenia, thrombosis, and systemic shock

GRK6 regulates the hemostatic response to injury through its rate-limiting effects on GPCR signaling in platelets

Platelets disseminate extracellular vesicles in lymph in rheumatoid arthritis

Cleavage of anti-PF4/heparin IgG by a bacterial protease and potential benefit in heparin-induced thrombocytopenia

The protease-activated receptor 4 Ala120Thr variant alters platelet responsiveness to low-dose thrombin and protease-activated receptor 4 desensitization, and is blocked by non-competitive P2Y12 inhibition

Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration

5B9, a monoclonal antiplatelet factor 4/heparin IgG with a human Fc fragment that mimics heparin-induced thrombocytopenia antibodies

Erratum: TULA-2 protein phosphatase suppresses activation of Syk through the GPVI platelet receptor for collagen by dephosphorylating Tyr(P)346, a regulatory site of Syk (The Journal of Biological Chemistry (2016) 291 (22427-22441) DOI: 10.1074/jbc.M116.743732)

Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia

TULA-2 (T-Cell Ubiquitin Ligand-2) Inhibits the Platelet Fc Receptor for IgG IIA (FcγRIIA) Signaling Pathway and Heparin-Induced Thrombocytopenia in Mice

TULA-2 protein phosphatase suppresses activation of syk through the GPVI platelet receptor for collagen by dephosphorylating Tyr(P)346 a regulatory site of syk

Mice expressing low levels of CalDAG-GEFI exhibit markedly impaired platelet activation with minor impact on hemostasis

Identification of novel Syk-independent functional roles of FcγRIIa in platelet outside-in signaling using transgenic mice expressing human FcγRIIa

Syk inhibition in ischemic stroke

Platelet transactivation by monocytes promotes thrombosis in heparin-induced thrombocytopenia

The antigenic complex in HIT binds to B cells via complement and complement receptor 2 (CD21)

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

Advances in the pathophysiology and treatment of heparin-induced thrombocytopenia

Lab Members

Steven E. McKenzie, MD PhD
Shaji Abraham, PhD

Shaji Abraham, PhD
Research Assistant

Shaji Abraham, PhD

Robert Kilker, MS
Research Technician

Stephanie Renna
PhD Student

Ulhas P. Naik, PhD


The Naik laboratory is focused on developing therapeutic strategies to interrupt the progress of cardiovascular diseases and cancer, which are the leading causes of death in the western world. In this regard, the team has identified several novel gene products that play key regulatory roles in the progression of these diseases, with an emphasis on how these genes affect platelet functions (since platelet activity often potentiates these diseases). Using cell and molecular biological approaches, the team has characterized the potential role of calcium- and integrin-binding (CIB) protein family and junctional adhesion molecule (JAM) family members in physiological and pathological settings. Cutting edge technologies, such as the yeast two-hybrid system, siRNA, transgenic mouse models, CRISPR/Cas9, and in vivo disease models are routinely employed in the laboratory. Dr. Naik is also the Director of the Cardeza Center for Vascular Biology, Director of Integrative Physiology Graduate Program, and a member of the following Graduate Programs:

Genetics, Genomics and Cancer Biology
Cell Biology and Regenerative Medicine
Biochemistry and Molecular Pharmacology

Our three major ongoing projects are:

Positive and negative regulatory mechanisms of platelet activation during thrombosis.

Our team has identified numerous novel regulators of platelet activity genetic ablation of which has shown protection from thrombosis (e.g. Cib1 [Naik MU, et al., 2009] and Ask1 [Naik MU, et al., 2017]) or amplification of platelet function (e.g. JAM-A [Naik MU, et al., 2012]). For example, the adjacent image from Naik MU, et al., 2017 shows how in a model of pulmonary thromboembolism, whereby clots are induced to form in the tail vein and subsequently lodge in the lungs leading to breathing cessation, Ask1 knockout mice have a much higher survival rate than their wildtype counterparts; hence deletion of Ask1 protects from thrombosis. Currently, several other genes products are being investigated through exciting in vitro, ex vivo, and in vivo methods, including carotid artery injury, cremaster injury, stroke, and Deep Vein Thrombosis models.

Regulation of new blood vessel formation (angiogenesis) by Junctional Adhesion Molecule A (JAM-A).  

We have cloned and characterized a novel junctional adhesion molecule, JAM-A (Naik, U.P., et al., Biochem. J. 1995; Naik, U.P., et al., J. Cell Sci, 2001; Naik, U.P. and Eckfeld, K. J. Biol. Regul. Homeost. Agents, 2003). JAM-A is expressed in endothelial and epithelial cells and resides at the tight junctions. We were the first to demonstrate that JAM-A regulates bFGF-induced angiogenesis through its interaction with integrin alphavbeta3 (Naik, M., et. al., Blood, 2003; Naik, M. and Naik, U.P., J. Cell Sci. 2006). Using siRNA and Jam-A knockout mouse, we have shown that JAM-A is essential for bFGF-induced angiogenesis (Naik, M., et al., Arterioscler Thromb. Vasc. Biol, 2003,; Cooke, et al., Arterioscler Thromb. Vasc. Biol, 2006). We extended this work further to demonstrate that JAM-A suppresses VEGF/VEGFR2 expression on endothelial cells, thus regulating vascular permeability and angiogenesis.

Mechanism of breast and prostate cancer cell metastasis.

Recently, we have found that JAM-A expression is inversely related to the metastatic ability of breast cancer cells (Naik, M., et al., Cancer Res. 2008). Overexpression of JAM-A in highly metastatic cells reduced their invasiveness; conversely, the knock-down of JAM-A in low metastatic cells increased their invasiveness. Studies are now ongoing to elucidate the molecular mechanism of this regulation. Furthermore, in collaboration with Justin Lathia of Cleveland Clinic, it has been shown that JAM-A regulates cancer stem cell function (Lathia, et al., Cell Rep, 2014).

Current Projects

2P20 RR015588-10
1R01 HL113118-02
1R01 HL119374-01
AHA Grant-in-Aid
Fraunhofer-UD Research Grant

Recent Publications

Junctional adhesion molecules in cancer: A paradigm for the diverse functions of cell-cell interactions in tumor progression

Apoptosis signal-regulating kinase 1 regulates immune-mediated thrombocytopenia, thrombosis, and systemic shock

JAM-A functions as a female microglial tumor suppressor in glioblastoma

Platelet MAPKs—a 20+ year history: What do we really know?

Retraction: Obesity-induced endoplasmic reticulum stress causes lung endothelial dysfunction and promotes acute lung injury

GRK6 regulates the hemostatic response to injury through its rate-limiting effects on GPCR signaling in platelets

The histone deacetylase inhibitor tubacin mitigates endothelial dysfunction by up-regulating the expression of endothelial nitric oxide synthase

Calcium-induced dissociation of CIB1 from ASK1 regulates agonist-induced activation of the p38 MAPK pathway in platelets

PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway: comment

CIB1 protects against MPTP-induced neurotoxicity through inhibiting ASK1

Obesity-induced endoplasmic reticulum stress causes lung endothelial dysfunction and promotes acute lung injury

Binding of CIB1 to the aIIb tail of aIIbβ3 is required for FAK recruitment and activation in platelets

Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation

Effect of Vorapaxar Alone and in Combination with Aspirin on Bleeding Time and Platelet Aggregation in Healthy Adult Subjects

Bacteria exploit platelets

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

Manipulating integrin signaling for anti-thrombotic benefits

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

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

Lab Members

Ulhas P. Naik, PhD
Kalyan Golla, PhD

Kalyan Golla, PhD
Postdoctoral Fellow

Meghna U. Naik, MSc

Meghna U. Naik, MSc
Research Lab Manager


Pravin Patel, BS
PhD Student


Noor Shaik, BS
MD/PhD Student


Latoya Watkins, BS
MS Student