1. IL-32 in inflammatory diseases. IL-32 is a pro-inflammatory cytokine that is elevated in a number of inflammatory human diseases. Interestingly, IL-32 is present in humans, but absent in rodents. The purpose of this project was to understand the role and mechanism of IL-32 in vascular inflammation in order to generate better mouse models for modeling human diseases. Unfortunately, our 2012 site visit committee suggested us to discontinue this line of research. To comply with this, we are trying to finish studies we have already started. This is important not only to avoid wasting resources we have used for this project, but also important for post-doc fellows who had worked on this project to publish the findings. Currently, we are in the process to summarize the findings into two manuscripts. In collaboration with Dr. Howard Young at the CCR and Dr. Alevizos Ilias in the Clinical Center, we found that IL-32 is elevated in patient with Sjogren's syndrome, and IL-32 promotes autoimmune phenotype via regulation of B cell migration and function. Lymphatic networks are essential for tissue homeostasis. Directional lymphatic flow is partially controlled by lymphatic valves. Our findings suggest a novel role of IL-32 in regulation of lymphatic valve formation via VEGFR3/NFATc1/FoxC2 signaling. 2. Interaction of Vav and delta-catenin in vascular formation and vascular homeostasis. Based on our site visit committee's recommendation, we reposition our focus on this line of research in the past physical year. Vascular formation is essential for tissue growth, repair and regeneration. What distinguishes physiological angiogenesis during normal development from pathological angiogenesis in disease conditions is a very important question. It has significant implications for therapeutic interventions. We reported that delta-catenin, a neuronal catenin, is also expressed in vascular endothelial cells, and deletion of only one allele of delta-catenin in mice is sufficient to impair endothelial cell motility and vascular assembly in vitro and pathological angiogenesis in vivo, thereby inhibiting tumor growth. In contrast, deletion of one or both allele of delta-catenin had no effects on hormone-induced physiological angiogenesis in the uterus. Because only pathological angiogenesis is sensitive to decreased levels of delta-catenin, this may provide a good target for anti-angiogenic therapy. Further analysis suggests that delta-catenin regulates RhoGTPase activity via interacting with Vav1, a guanine nucleotide exchange factor (GEF). Vav1 is specifically expressed in hematopoietic cells and regulates cell differentiation. Since hematopoietic cells and endothelial cells share a common progenitor, Vav1 was also implicated in vascular endothelium. However, its function in the vasculature is totally unknown. To systemically and thoroughly study the role and mechanism of Vav1 in vascular biology, we have generated conditional Vav1 null and conditional Vav1 transgenic mouse lines during this physical year. Vav1 is known to be present in hematopoietic cells. We showed expression of Vav1 in vascular endothelial cells. However, it is currently unknown if Vav1 is also expressed in other cell lineages considering reports of Vav1 expression in several epithelial cancer cells. The Vav1 mouse lines we developed will allow us to systemically analyze Vav1 expression during development and disease conditions since a reporter gene was introduced in the mice under the endogenous Vav1 promoter. They will allow us to investigate Vav1 function and mechanisms in a cell type specific manner. In combination of cell/organ cultures and genetically engineered mice, we have demonstrated that 1) Vav1 regulates endothelial cell motility and angiogenesis via its GEF function for RhoGTPase;2) Vav1 regulates vascular permeability through stabilization VE-Cadherin junctions on cell surface;3) Vav1 regulates eNOS activation via Sirt1 thereby regulating vascular function and homeostasis;and 4) Vav1 regulates endothelial progenitor cell production and mobilization (vasculogenesis) via regulating CXCR4 expression and MMP9 activation in bone marrow derived vascular progenitor cells. Interestingly, 5) we found high levels of Vav1 expression in mesenchymal stem cells (MSC). Vav1 plays opposite roles in MSC differentiation toward adipocyte in comparison to chondrocyte and osteocyte. Together, these findings illustrate important and complex functions of Vav1 and delta catenin interaction in vascular formation and integrity. Currently, we are in the process to summarize these novel findings into multiple manuscripts for publication. Collaborations To ensure successful progress in research, we have worked closely with investigators within the NIH and extramural community. We have been working with Drs. Howard Young and Alevizos Ilias at the NIH, and Dr. Michelle Petri at the Johns Hopkins University on autoimmune studies;with Dr. Dan E. Berkowitz at the Johns Hopkins University on Vav1/eNOS signaling and vascular functions;with Drs. Hans Schreiber at the University of Chicago and Tomasz Zal at the MD Anderson Cancer Center on real-time in vivo imaging of cancer variant elimination through T cell-mediated stromal targeting;with Dr. Vladimir R. Babaev at the Vanderbilt University on macrophage IKK-Akt signaling in atherosclerosis development;and Dr. Emily Wang at the City of Hope National Medical Center on cancer cell-derived miR-105 in promoting tumor invasion through destroying the natural barriers against metastasis.
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