Cellular and Genetic Analysis of Lymphocyte Egress

淋巴细胞排出的细胞和遗传分析

• 批准号: 9066060
• 负责人: Jason G Cyster
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066060
• 关键词: Address; Antigens; Autoimmune Diseases; Award; B-Lymphocytes; Blood; Blood Circulation; Blood-Borne Pathogens; Cells; Clinical; Data; Dendritic Cells; Development; Effector Cell; Epithelium; Goals; Grant; Immune; Immune System Diseases; Immune response; Immunologic Surveillance; Immunosuppressive Agents; Infection; Inflammatory; Knowledge; Ligands; Lymph; Lymphatic; Lymphatic Endothelium; Lymphatic vessel; Lymphocyte; Lymphoid; Lymphoid Tissue; Malpighian corpuscles; Microscopy; Modeling; Molecular; Movement; Oral; Organ; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Procedures; Role; Site; Skin; Source; Sphingosine-1-Phosphate Receptor; Spleen; Splenic Red Pulp; Structure of aggregated lymphoid follicle of small intestine; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Thymus Gland; Time; Tissue Model; Tissues; Travel; Work; cell motility; cell type; follow-up; genetic analysis; immune function; intravital microscopy; lymph nodes; migration; multiple sclerosis treatment; novel therapeutics; response; sphingosine 1-phosphate; targeted treatment; therapeutic development; tool; trafficking; two-photon

DESCRIPTION (provided by applicant): The molecular mechanism of cell entry from blood into tissues has been intensely studied over more than three decades. This work has led to a well-defined multistep model of tissue entry by cells and the development of approved therapeutic agents that target entry as a treatment for immunological diseases. Cell egress from tissues into circulation is equally important for immune function yet has been a focus of study for only the last several years. The potential clinical impact of developing agents to modulate cell egress has been highlighted by the September 2010 approval of FTY720 (Fingolimod), a drug that inhibits lymphocyte egress from lymphoid organs, as the first oral treatment for multiple sclerosis. FTY720 is a ligand for four of five sphingosine-1-phosphate (S1P) receptors. T and B cell egress from lymph nodes, spleen and Peyer's patches is dependent on S1P and S1P receptor-1 (S1PR1). This proposal will identify the pathway of B cell egress from the spleen into blood. Secondly, it will characterize how S1PR1 regulates marginal zone B cell movement and antigen transport between subcompartments within the spleen. Thirdly, it will explore the role of a migration- inhibitory S1P receptor, S1PR2, in controlling egress of cells from non-lymphoid tissues into lymph. This work will elucidate key requirements for lymphocyte egress from lymphoid and non-lymphoid tissues, findings that may help in the development of new therapeutics for treatment of autoimmune diseases.

描述(申请人提供)：细胞从血液进入组织的分子机制已经被深入研究了三十多年。这项工作导致了一个明确的细胞进入组织的多步骤模型，并开发了以细胞进入为目标的治疗免疫性疾病的已获批准的治疗剂。细胞从组织进入循环对免疫功能同样重要，但一直是研究的重点 只在过去几年里。2010年9月，FTY720(Fingolimod)被批准作为多发性硬化症的首个口服治疗药物，这突显了开发调节细胞外流的药物的潜在临床影响。FTY720(Fingolimod)是一种抑制淋巴细胞从淋巴器官外流的药物。FTY720是五种鞘氨醇-1-磷酸(S1P)受体中四种的配体。淋巴结、脾和Peyer‘s结的T、B细胞输出依赖于S1P和S1P受体-1(S1PR1)。这一建议将确定B细胞从脾进入血液的途径。其次，它将描述S1PR1如何调节边缘区域B细胞的运动和脾内各亚室之间的抗原运输。第三，它将探索迁移抑制S1P受体S1PR2在控制细胞从非淋巴组织进入淋巴中的作用。这项工作将阐明淋巴细胞从淋巴组织和非淋巴组织中流出的关键要求，这一发现可能有助于开发治疗自身免疫性疾病的新疗法。

项目成果

The C2H2-ZF transcription factor Zfp335 recognizes two consensus motifs using separate zinc finger arrays.

• DOI: 10.1101/gad.279406.116
• 发表时间: 2016-07-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Han BY;Foo CS;Wu S;Cyster JG
• 通讯作者: Cyster JG

Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction.

• DOI: 10.1126/science.1188222
• 发表时间: 2010-05-28
• 期刊: Science (New York, N.Y.)
• 作者: Zachariah MA;Cyster JG
• 通讯作者: Cyster JG

CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function through interaction with membrane helix 4.

• DOI: 10.1074/jbc.m110.123299
• 发表时间: 2010-07-16
• 期刊: The Journal of biological chemistry
• 作者: Bankovich AJ;Shiow LR;Cyster JG
• 通讯作者: Cyster JG

GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood.

• DOI: 10.1126/science.1208248
• 发表时间: 2011-09-30
• 期刊: Science (New York, N.Y.)
• 作者: Arnon TI;Xu Y;Lo C;Pham T;An J;Coughlin S;Dorn GW;Cyster JG
• 通讯作者: Cyster JG