Philadelphia University + Thomas Jefferson University
Sidney Kimmel Medical College
Department of Medicine

Horowitz, Arie

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Arie Horowitz, DSc

Arie Horowitz, DSc

Contact Dr. Horowitz

1020 Locust Street
Suite 394
Philadelphia, PA 19107

(215) 955-8017
(215) 955-9170 fax

Research & Clinical Interests

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 Blazewska 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.


Most Recent Peer-Reviewed Publications

  1. Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease
  2. Analysis of retinoic acid-induced neural differentiation of mouse embryonic stem cells in two and three-dimensional embryoid bodies
  3. Letter by Horowitz Regarding Article, "protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability"
  4. The versatility of RhoA activities in neural differentiation
  5. RhoA inhibits neural differentiation in murine stem cells through multiple mechanisms
  6. The cytoplasmic domain of neuropilin-1 regulates focal adhesion turnover
  7. VEGF and angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx
  8. Stimulus-dependent phosphorylation of profilin-1 in angiogenesis
  9. Regulation of VEGF signaling by membrane traffic
  10. Rab13-dependent trafficking of RhoA is required for directional migration and angiogenesis
  11. Erratum: Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways (Circulation Research (2008) 103 (e71-e79))
  12. Imaging of growth factor-augmented angiogenesis after myocardial infarction: glimmers of a spatiotemporal pattern?
  13. Cleavage of syndecan-4 by ADAMTS1 provokes defects in adhesion
  14. Branching morphogenesis
  15. The Amot/Patj/Syx signaling complex spatially controls RhoA GTPase activity in migrating endothelial cells
  16. Branching morphogenesis
  17. Syx, a rhoA guanine exchange factor, is essential for angiogenesis in vivo
  18. Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways
  19. Directional cues in angiogenesis
  20. 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)