A5063010182- Angiogenesis and VEGF in Cancer
- Cancer, Lipids, and Metabolism
- Congenital heart defects research
- Cell Adhesion Molecules Research
- Cytokine Signaling Pathways and Interactions
- Immune Cell Function and Interaction
- Venous Thromboembolism Diagnosis and Management
- Kruppel-like factors research
- MicroRNA in disease regulation
- CAR-T cell therapy research
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- Cancer Cells and Metastasis
- Cancer-related gene regulation
- Cancer-related molecular mechanisms research
- Vector-borne infectious diseases
- Cancer Immunotherapy and Biomarkers
- Acute Lymphoblastic Leukemia research
- Wnt/β-catenin signaling in development and cancer
- Cancer, Hypoxia, and Metabolism
- Renal and related cancers
- Hematopoietic Stem Cell Transplantation
- Renal Diseases and Glomerulopathies
- Virus-based gene therapy research
- Protease and Inhibitor Mechanisms
Regeneron (United States)
2012-2024
Stanford University
2003-2017
Stanford Medicine
2007-2011
Scripps Research Institute
2004-2010
Army Medical University
2010
Cornell University
2010
Icahn School of Medicine at Mount Sinai
1999-2005
Howard Hughes Medical Institute
2003
Universitätsklinikum Tübingen
1998
University of Neuchâtel
1995-1996
Despite the importance of CNS blood vessels, molecular mechanisms that regulate angiogenesis and blood-brain barrier (BBB) formation are largely unknown. Here we analyze role Wnt/beta-catenin signaling in regulating vessels. First, through analysis TOP-Gal Wnt reporter mice, identify canonical is specifically activated CNS, but not non-CNS, vessels during development. This activation correlates with expression different ligands by neural progenitor cells distinct locations throughout...
Whereas the adult gastrointestinal epithelium undergoes tremendous self-renewal through active proliferation in crypt stem cell compartments, responsible growth factors regulating this continuous have not been defined. The exploration of physiologic functions Wnt proteins organisms has hampered by functional redundancy and necessity for conditional inactivation strategies. Dickkopf-1 (Dkk1) is a potent secreted antagonist that interacts with coreceptors LRP family. To address contribution...
Intronic microRNAs have been proposed to complicate the design and interpretation of mouse knockout studies. The endothelial-expressed Egfl7/miR-126 locus contains miR-126 within Egfl7intron 7, angiogenesis deficits previously ascribed Egfl7 gene-trap lacZ knock-in mice. Surprisingly,selectively floxed Egfl7Δ miR-126Δ alleles revealed that Egfl7Δ/Δ mice were phenotypically normal, whereas miR-126Δ/Δ bearing a 289-nt microdeletion recapitulated described embryonic postnatal retinal vascular...
The orphan G protein-coupled receptor (GPCR) GPR124/tumor endothelial marker 5 is highly expressed in central nervous system (CNS) endothelium. Here, we show that complete null or endothelial-specific GPR124 deletion resulted embryonic lethality from CNS-specific angiogenesis arrest forebrain and neural tube. Conversely, overexpression throughout all adult vascular beds produced hyperproliferative malformations. In vivo, functioned cell-autonomously endothelium to regulate sprouting,...
Mouse embryonic stem cells are pluripotent that derived from the inner cell mass of blastocysts. When induced to synchronously enter a program differentiation in vitro, they form embryoid bodies contain mesodermal, hematopoietic, endothelial, muscle, and neuronal lineages. Here, we used panel marker genes with early expression within germ layers (oct-3, Brachyury T, Fgf-5, nodal, GATA-4) or variety lineages (flk-1, Nkx-2.5, EKLF, Msx3) determine how progressive culture correlated...
Tumor angiogenesis is an important target for cancer therapy, with most current therapies designed to block the VEGF signaling pathway. However, clinical resistance anti-VEGF therapy highlights need targeting additional tumor pathways. The endothelial Notch ligand Dll4 (delta-like 4) has recently emerged as a critical regulator of and thus promising new therapeutic anti-angiogenesis target. Blockade Dll4-Notch in tumors results excessive, non-productive resultant inhibitory effects on...
Abstract We report the cloning and characterization of a novel epidermal growth factor (EGF) domain gene that was identified in retroviral entrapment screen is expressed endothelial cells. This encodes protein 278 amino acids with an amino‐terminal signal peptide two centrally located EGF‐like domains. have named this accordance guidelines Mouse Genome Informatics group Egfl7 , for EGF ‐ l ike 7. mRNA highly vascularized adult tissues such as lung, heart, uterus, ovary. In addition, early...
The simultaneous targeting of both endothelial cells and pericytes via inhibition VEGF receptor (VEGFR) PDGFbeta (PDGFRbeta) signaling, respectively, has been proposed to enhance the efficacy antiangiogenic tumor therapy. Clinical preclinical modeling combined VEGFR PDGFRbeta signaling inhibition, however, used small molecule kinase inhibitors with inherently broad substrate specificities, precluding detailed examination this hypothesis. Here, adenoviral expression a soluble VEGFR2/Flk1...
Background The Notch ligand Delta-like 4 (Dll4) is highly expressed in vascular endothelium and has been shown to play a pivotal role regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway preclinical cancer models associated with non-productive angiogenesis reduced growth. Given cross-talk between endothelial growth factor (VEGF) Delta-Notch pathways angiogenesis, we examined activity function-blocking Dll4 antibody, REGN1035, alone combination anti-VEGF therapy renal cell...
Vascular endothelial growth factor (VEGF), platelet-derived (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear whether inhibition of VEGF PDGF together more effective than either one alone. Here, we used two contrasting tumor models to compare the effects inhibiting or alone, by adenovirally generated soluble receptors, both together. In RIP-Tag2 tumors, reduced vascularity abundance pericytes. without decreasing...
Abstract The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), fully human IgG1 monoclonal antibody that binds with sub-nanomolar affinity inhibits signaling. Administering to immunodeficient mice engineered express inhibited growth several xenografts...
Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic transplantation (allo-HCT) in mice, with a dominant role for the Delta-like ligand DLL4. To assess whether Notch’s effects are evolutionarily conserved to identify mechanisms of inhibition, we studied antibody-mediated DLL4 blockade nonhuman primate (NHP) model similar human allo-HCT. Short-term improved posttransplant survival durable protection from gastrointestinal GVHD...
Abstract The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis better responses to immune checkpoint blockade many cancer types. Elucidation the molecular mechanisms underlying intratumoral HEV TLS formation their contribution antitumor may facilitate development improved treatment strategies. Lymphotoxin β receptor (LTβR) signaling a critical regulator lymph node organogenesis can cooperate antiangiogenic...
Vezf1 encodes an early zinc finger transcription factor that is essential for normal vascular development and functions in a dose-dependent manner. Here, we investigated the role of during processes endothelial cell differentiation maturation by studying mutant embryonic stem (ES) cells using vitro embryoid body model vivo teratocarcinoma model.Vezf1-/- ES cell-derived bodies failed to form well-organized network showed dramatic sprouting defects. Our results indicate retinol pathway...