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One or more keywords matched the following properties of Shenkar, Robert
keywords Laboratory Mice
overview 1. Focus on signaling and therapy in cerebral cavernous malformations. 2. Focus on biomarkers of cerebral cavernous malformations. 3. Focus on inflammation in cerebral cavernous malformations. Several approaches are being used to conduct research on cerebral cavernous malformations, including murine models, magnetic resonance imaging, electron microscopy and confocal microscopy. Disease of Interest: Cerebral cavernous malformation (CCM) is a vascular disorder of the brain affecting 0.5% of the population. CCM disease can either be sporadic or familial, resulting from haploinsufficiency in one of three genes, KRIT1/CCM1, CCM2 or PDCD10/CCM3. Symptoms are CCM disease include seizures, neurological deficits and/or hemorrhagic stroke. There is presently no therapy to prevent the development or clinical progression of CCM lesions. Current Projects: 1. ROCK Inhibition as Therapy for Cerebral Cavernous Malformation: We have shown that the loss of CCM proteins, KRIT1, CCM2 or PDCD10 activates RhoA and its downstream effector Rho kinase (ROCK). Increased vascular permeability in Krit1 and Ccm2 heterozygous mice is reversed by ROCK inhibition. ROCK activity is increased in human and mouse CCM endothelium. These observations led us to hypothesize that aberrant Rho activation causes CCM pathogenesis. We are currently conducting a cross sectional study on the effects of ROCK inhibition on CCM lesion burden. We are presently treating three CCM murine models (Krit1, Ccm2, Pdcd10) with the specific ROCK inhibitor fasudil, and the more pleiotropic ROCK inhibitors simvastatin and atorvastatin. After therapy, we are assessing the mouse brains for lesion burden, lesion area, iron deposition, inflammation, ultrastructure and endothelial junctional protein expression. In longitudinal studies we examine CCM lesions for growth and size, iron deposition and phenotypic markers after therapy in murine models after they are identified by magnetic resonance imaging in vivo, and the effects of therapy will be evaluated mechanistically through differential gene expression. Surgically resected human CCM lesions will be examined for differential expression and signaling pathways for ROCK related genes. 2. Biomarkers of Brain Permeability in Human Cerebral Cavernous Malformations: Our observations on the relationship between CCM proteins, endothelial permeability and ROCK activity suggest that both endothelial permeability and ROCK activity could be used as biomarkers for CCM disease. We are currently measuring vascular permeability in the brains of patients with CCM disease by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging. Because ROCK activity in leukocytes was shown to decrease by statins by our collaborator, Dr. James Liao, we are using leukocyte ROCK activity as a biomarker in patients with CCM disease. These techniques will allow us to assess brain vascular permeability and leukocyte ROCK activity as potential biomarkers for CCM disease severity in patients. 3. Inflammation in Cerebral Cavernous Malformation: My observation that immunoglobulins were among the most highly expressed genes in surgically resected human cerebral cavernous malformations, led our laboratory to show a robust presence of B, T and plasma cells in CCM lesions both from patients and murine models, and immune complexes in human lesions. Immunoglobulins from plasma cells in human CCM lesions were shown to be oligoclonal. The immunoglobulin variable region RNA isolated from plasma cells from human CCM lesions was sequenced and used to make recombinant antibodies, which may be used to identify the triggering antigen. We are presently pursuing the effect of B depletion on CCM lesions in murine models.
One or more keywords matched the following items that are connected to Shenkar, Robert
Item TypeName
Concept Mice, Inbred C3H
Concept Mice, Transgenic
Concept Mice, Inbred BALB C
Concept Mice, Inbred C57BL
Concept Mice, Inbred DBA
Concept Mice, Knockout
Concept Mice
Concept Mice, Mutant Strains
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Academic Article Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression.
Academic Article Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element binding protein.
Academic Article Interactions between CBP, NF-kappaB, and CREB in the lungs after hemorrhage and endotoxemia.
Academic Article Neutrophil apoptosis in the lung after hemorrhage or endotoxemia: apoptosis and migration are independent of interleukin-1beta.
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Academic Article Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury.
Academic Article Lipopolysaccharide-induced neutrophil gene expression under in vivo or in vitro conditions.
Academic Article Advanced magnetic resonance imaging of cerebral cavernous malformations: part II. Imaging of lesions in murine models.
Academic Article Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity.
Academic Article A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease.
Academic Article Fasudil decreases lesion burden in a murine model of cerebral cavernous malformation disease.
Academic Article Anti-transforming growth factor-beta monoclonal antibodies prevent lung injury in hemorrhaged mice.
Academic Article Hemorrhage and resuscitation induce alterations in cytokine expression and the development of acute lung injury.
Academic Article Cerebral cavernous malformations: clinical insights from genetic studies.
Academic Article Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice.
Academic Article Effects of treatment with the 21-aminosteroid, U7438F, on pulmonary cytokine expression following hemorrhage and resuscitation.
Academic Article Hyperoxia activates NF-kappaB and increases TNF-alpha and IFN-gamma gene expression in mouse pulmonary lymphocytes.
Academic Article Systemic blood loss affects NF-kappa B regulatory mechanisms in the lungs.
Academic Article Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury.
Academic Article DNase I-hypersensitive sites and transcription factor-binding motifs within the mouse E beta meiotic recombination hot spot.
Academic Article Cytokine expression in Peyer's patches following hemorrhage and resuscitation.
Academic Article Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.
Academic Article Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling.
Academic Article B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models.
Academic Article Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease.
Academic Article RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations.
Academic Article Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.
Academic Article Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations.
Academic Article Phenotypic characterization of murine models of cerebral cavernous malformations.
Academic Article Rho Kinase Inhibition Blunts Lesion Development and Hemorrhage in Murine Models of Aggressive Pdcd10/Ccm3 Disease.
Academic Article A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease.
Academic Article Transcriptome clarifies mechanisms of lesion genesis versus progression in models of Ccm3 cerebral cavernous malformations.
Academic Article Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.
Academic Article Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican.
Academic Article Novel Murine Models of Cerebral Cavernous Malformations.
Academic Article Propranolol inhibits cavernous vascular malformations by ß1 adrenergic receptor antagonism in animal models.
Academic Article PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism.
Academic Article Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation.
Academic Article Rapamycin in Cerebral Cavernous Malformations: What Doses to Test in Mice and Humans.
Academic Article Circulating Plasma miRNA Homologs in Mice and Humans Reflect Familial Cerebral Cavernous Malformation Disease.
Academic Article ß1 integrin monoclonal antibody treatment ameliorates cerebral cavernous malformations.
Academic Article mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.
Academic Article Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling.
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  • Laboratory Mice