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Endothelial Cell Biology in Inflammation

炎症中的内皮细胞生物学

基本信息

批准号：
8889128
负责人：
EUGENE C BUTCHER
金额：
$ 31.25万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-01-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8889128
关键词：
Address Adhesions Affinity Antigens Area Autoimmune Process B-Lymphocytes Binding Biology Blood Blood Vessels Blood capillaries Bone Marrow CD22 gene Capillary Endothelial Cell Carbohydrates Cardiovascular system Cell Line Cells Cellular biology Chemotactic Factors Chronic Code Cytokine Receptors Data Disease Elements Endothelial Cells Endothelium Enzymes Gene Expression Gene Expression Profile Genes Genetic Programming Genome Goals Gut associated lymphoid tissue Haptens Health High Endothelial Venule Homing Immune Immune response Immunization Immunology Inflammation Investigation Knockout Mice Lead Lectin Leukocyte Trafficking Leukocytes Ligands Lipids Lymphocyte Lymphocyte Subset Lymphoid Lymphoid Tissue Mesentery Metabolic Pathway Metabolism Mining Modeling Modification Molecular Molecular Profiling Organ Organ Specificity Outcome Pathologic Pathway interactions Pattern Peripheral Polysaccharides RNA marker Recruitment Activity Regulator Genes Rest Role Septic Shock Sialic Acids Sialyltransferases Signal Transduction Site Skin Sorting - Cell Movement Specific qualifier value Sterols Stromal Cells Structure of aggregated lymphoid follicle of small intestine Testing Tissues Translating adhesion receptor base capillary cell motility chemokine data mining fMet-Leu-Phe receptor in vivo insight leukocyte homing lipid metabolism lymph nodes migration novel novel marker novel therapeutic intervention pathogen programs receptor response sulfation sulfotransferase transcription factor transcriptomics vascular addressins

项目摘要

Our overall goal is to elucidate the functional and transcriptomic specialization of endothelial cells (EC) that recruit lymphocytes from the blood, and to define novel mechanisms involved in lymphocyte homing via high endothelial venules (HEV). In addition to differences from capillary (CAP) and other EC, HEV display tissue-specific expression of vascular “addressins”, adhesion receptors and chemokines that control the organ specificity of lymphocyte homing. To identify genes and transcriptional networks that define and program HEV specialization, we have initiated whole genome expression studies of lymphoid tissue HEV and CAP. Preliminary data mining has identified novel candidate mechanisms for the control of lymphocyte recruitment, including a novel vascular addressin for B cell homing and HEV expression of genes for metabolism of lipid regulators of diapedesis. Aims include: 1) To comprehensively analyze the segmental (HEV vs CAP) and tissue-specific (skin- draining vs mesenteric lymph node and Peyer’s patch) transcriptional specialization of HEC, and to define the response of HEC to immunization. HEC and CAP from dissociated PLN, MLN and PP will be sorted by FACS based on EC subset markers, and RNA submitted for whole genome expression profiling. The transcriptional response of HEC to polarizing immune responses will be defined by comparison of HEV and CAP from resting vs immunized LN. 2) To elucidate the biosynthetic machinery required for HEV synthesis of a novel carbohydrate vascular addressin for B cell homing. Our gene expression data led to discovery of a Gal2, 6 sialyltransferase-dependent PP HEV ligand for the B cell lectin Siglec2 (CD22). We will use CD22-Fc binding in studies of St6gal1, Cmah and CHST 2±4 sulfotransferase knockout mice to test the hypothesized roles of HEV-expressed glycan-modifying enzymes in synthesis of the novel addressin. 3) To test the hypothesis that HEV-associated lipid metabolites regulate lymphocyte migration from HEC. Based on transcriptional analyses of enzyme expression by HEC and surrounding cells, we hypothesize that gradients of lipid chemoattractants participate in lymphocyte recruitment via HEV. Lymphocyte diapedesis during short term homing will be quantified, and the effects of deficiency in lymphocyte receptors and/or inhibition of targeted metabolic pathways in recipient lymph nodes will be assessed. Comprehensive analyses of HEV and CAP transcriptomes will open up new areas of investigation in vascular biology and immunology. Elucidation of the mechanisms of vascular control of lymphocyte recruitment may lead to novel targets and approaches for the control of autoimmune and other pathologic inflammation.

我们的总体目标是阐明内皮细胞（EC）的功能和转录组特化