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Transcriptional Profiling of Human High Endothelial Venules

人类高内皮小静脉的转录谱

基本信息

批准号：
9212639
负责人：
EUGENE C BUTCHER
金额：
--
依托单位：
VETERANS ADMIN PALO ALTO HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212639
关键词：
ATAC-seq Adenoidal structure Adhesions Affect Alzheimer&apos s Disease Animal Model Animals Antibodies Area Arthritis Autoimmune Process Autopsy Binding Biology Blood Blood Vessels Blood capillaries CCL21 gene Capillary Endothelial Cell Cardiovascular Diseases Cardiovascular system Cell Communication Cell Separation Cells Chromatin Chronic Clinical Data Diabetes Mellitus Disease Dissociation Distal Drug Targeting Endothelial Cells Endothelium Enhancers Enzymes Epithelial Gene Expression Gene Expression Regulation General Population Genes Genetic Transcription Goals Gut associated lymphoid tissue High Endothelial Venule Homing Human Immune Immune response Immunology Inflammation Inflammation Process Inflammatory Inflammatory Bowel Diseases Inflammatory Response Investigation L-Selectin Lead Leukocyte Trafficking Leukocytes Literature Lymphocyte Lymphoid Tissue Maps Mediating Molecular Molecular Profiling Mus Ontology Operative Surgical Procedures Organ Organ Specificity Outcome PECAM1 gene PNAd Pathologic Pathway interactions Pattern Peripheral Protocols documentation RNA Recruitment Activity Resources Signal Pathway Site Specimen Surface Tissue Procurements Tissues Tonsil Translating Translations Vascular Endothelium Veterans adhesion receptor candidate marker capillary chemokine epigenomics genetic signature insight lymph nodes man novel postcapillary venule programs promoter public health relevance receptor selective expression species difference targeted treatment therapeutic target trafficking transcription factor transcriptome transcriptomics vascular addressins whole genome

项目摘要

DESCRIPTION (provided by applicant): Our goal is to elucidate the transcriptional specialization of human high endothelial venules (HEV), unique post-capillary venules that control lymphocyte homing and thus immune and inflammatory responses. Most studies of HEV, and the only comprehensive studies of gene expression by HEV, have been carried out in mice: relatively little is known about human HEV or indeed, about the gene programs underlying the segmental and tissue specialization of blood endothelial cells in man. Notably, several vascular molecules implicated in lymphocyte homing in the mouse, including the peripheral lymph node "addressin", VAP1, CCL21 and others, are regulated differently in humans. We recently completed comprehensive transcriptomic studies of mouse lymphoid tissue high endothelial cells (HEC) and enriched capillary EC (CAP). Here we shall apply our established protocols to perform whole genome expression analyses of human lymphoid tissue HEV and CAP. Aims include: 1) To perform whole genome expression profiling of high endothelial cells (HEC) and capillary endothelial cells (CAP) from human tonsils, adenoids, peripheral lymph nodes (PLN), and appendix. We will apply existing protocols for endothelial dissociation from fresh human lymphoid tissues, and will purify HEC and capillary EC using FACS cell sorting protocols with established HEC and pan-EC markers. RNA will be submitted for whole genome expression profiling. 2) To define the segmental (HEV vs CAP) and tissue-specific (tonsil or adenoid, PLN, appendix) transcriptional specialization of human high endothelial cells (HEC). We shall elucidate vascular programs that define HEC specialization (and thus lymphocyte homing) by comparing the transcriptomes of HEC and of capillary endothelium (CAP), which unlike HEC inhibit leukocyte adhesion. We will also identify gene sets expressed in HEC in a tissue-specific fashion, genes likely to encode mechanisms that control vascular addressins or chemo attractants for tissue-specific lymphocyte recruitment. 3) To compare and contrast human vs. mouse HEV-, CAP- and tissue-specific HEC gene signatures, and to identify evolutionarily conserved transcriptional programs of HEC. We shall define differences in HEC gene expression in humans vs. mice, the most studied animal model. We will identify genes with conserved patterns of HEC vs CAP, or of tissue-specific HEC expression: such genes are likely to encode molecular mechanisms (transcription factors, adhesion or attractant molecules, signaling pathways) critical to HEV function. Comprehensive analyses of human HEV and capillary EC transcriptomes will open up new areas of investigation in vascular biology and immunology, and will inform efforts to translate mouse studies to the clinical arena. The data generated will constitute a valuable resource for elucidation of mechanisms of vascular control of lymphocyte recruitment, and may lead to novel targets and approaches for the control of autoimmune and other pathologic inflammatory disorders.

描述（由申请人提供）：我们的目标是阐明人类高内皮微静脉（HEV）的转录特化，独特的毛细血管后微静脉控制淋巴细胞归巢，从而免疫和炎症反应。大多数关于戊型肝炎病毒的研究，以及关于戊型肝炎病毒基因表达的唯一综合性研究，都是在小鼠中进行的：关于人HEV或实际上关于人血液内皮细胞的节段和组织特化的基因程序所知相对较少。值得注意的是，涉及小鼠淋巴细胞归巢的几种血管分子，包括外周淋巴结“地址素”、VAP 1、CCL 21等，在人类中的调节方式不同。我们最近完成了小鼠淋巴组织高内皮细胞（HEC）和富集毛细血管EC（CAP）的全面转录组学研究。在这里，我们将应用我们建立的协议进行全基因组表达分析的人淋巴组织HEV和CAP。目标包括：1）对来自人扁桃体、腺样体、外周淋巴结（PLN）和阑尾的高内皮细胞（HEC）和毛细血管内皮细胞（CAP）进行全基因组表达谱分析。我们将应用现有的协议，从新鲜的人淋巴组织内皮细胞解离，并将纯化HEC和毛细血管EC使用流式细胞仪细胞分选协议与已建立的HEC和泛EC标记。将提交RNA进行全基因组表达谱分析。2)明确人高内皮细胞（HEC）的节段性（HEV vs CAP）和组织特异性（扁桃体或腺样体、PLN、阑尾）转录特化。我们将阐明血管计划，定义HEC的专业化（从而淋巴细胞归巢），通过比较转录组的HEC和毛细血管内皮细胞（CAP），这不同于HEC抑制白细胞粘附。我们还将确定在HEC中以组织特异性方式表达的基因组，这些基因可能编码控制血管地址素或组织特异性淋巴细胞募集的化学引诱剂的机制。3)比较和对比人类与小鼠HEV、CAP和组织特异性HEC基因特征，并鉴定HEC进化上保守的转录程序。我们将定义人类与小鼠（研究最多的动物模型）中HEC基因表达的差异。我们将确定HEC与CAP或组织特异性HEC表达的保守模式的基因：这些基因可能编码对HEV功能至关重要的分子机制（转录因子，粘附或引诱分子，信号通路）。对人HEV和毛细血管EC转录组的综合分析将开辟血管生物学和免疫学研究的新领域，并将为将小鼠研究转化为临床竞技场的努力提供信息。所产生的数据将构成一个宝贵的资源，阐明淋巴细胞募集的血管控制机制，并可能导致新的目标和方法控制自身免疫性和其他病理性炎症性疾病。