Cellular and Genetic Analysis of Lymphocyte Egress

淋巴细胞排出的细胞和遗传分析

• 批准号: 7298060
• 负责人: Jason G Cyster
• 金额: $ 37.95万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7298060
• 关键词: Activated Lymphocyte; Address; Australia; B-Lymphocytes; Blood; Blood Circulation; Cataract; Cell physiology; Cells; Clinical; Clinical Trials; Collaborations; Complex; Defect; Development; Effector Cell; Exhibits; G Protein-Coupled Receptor Genes; Genetic; Image; Immunologic Surveillance; Immunosuppression; Immunosuppressive Agents; Integral Membrane Protein; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Lymphoid; Maps; Mediating; Molecular; Multiple Sclerosis; Mus; Mutant Strains Mice; Organ; Patients; Production; Regulation; Role; Sphingosine-1-Phosphate Receptor; T-Lymphocyte; Testing; Therapeutic immunosuppression; Thymus Gland; Tissues; Transplantation; Work; genetic analysis; in vivo; lymph nodes; novel; small molecule; trafficking

DESCRIPTION (provided by applicant): T and B cell egress from lymphoid organs is necessary for immune surveillance and effector cell function. Work over the last 25 years has provided a detailed cellular and molecular picture for how cells enter tissues from the blood. By contrast, very little has been defined about how cells exit tissues and return to circulation. The clinical importance of lymphocyte egress and lymphocyte recirculation has been revealed by the finding that the immunosuppressive molecule, FTY720, acts by inhibiting egress from lymphoid organs. Work over the last five years has established a critical role for S1P receptor-1 (S1P1) in lymphocyte egress from lymphoid organs. S1P1 has also been found to be a control point for egress regulation. The lymphocyte activation marker, CD69, acts as a negative regulator of S1P1 and lymphocyte egress. However, the mechanism by which lymphocyte S1P1 promotes egress, and the mode of CD69 mediated regulation of S1P1 remain undefined. This proposal will address the cellular and molecular requirements for lymphocyte egress and mechanisms associated with egress regulation through three specific aims. The first Aim will use a combination of cellular and multiphoton imaging approaches to characterize the S1P1-dependent step in lymphocyte egress from lymph nodes. Aim 2 will focus on determining the mechanism of CD69 mediated inhibition of S1P1 function and lymphocyte egress. The final Aim will use genetic approaches to identify additional molecules required for lymphocyte egress. This aim will build upon a collaboration with Christopher Goodnow in Australia to identify and characterize mutant mouse lines that exhibit alterations in lymphocyte trafficking. As part of this effort we will fine map and characterize the locus responsible for the thymic egress defect in Cataract Shionogi (CTS) mice. The information obtained through these studies should point to new targets for the development of immunomodulatory molecules.

描述（由申请人提供）：T 细胞和 B 细胞从淋巴器官中流出对于免疫监视和效应细胞功能是必要的。过去 25 年的工作为细胞如何从血液进入组织提供了详细的细胞和分子图像。相比之下，关于细胞如何离开组织并返回循环的定义很少。免疫抑制分子 FTY720 通过抑制淋巴器官的流出发挥作用，这一发现揭示了淋巴细胞流出和淋巴细胞再循环的临床重要性。过去五年的工作已经确定了 S1P 受体 1 (S1P1) 在淋巴细胞从淋巴器官流出的过程中发挥着关键作用。 S1P1 也被发现是出口监管的控制点。淋巴细胞激活标记 CD69 充当 S1P1 和淋巴细胞排出的负调节因子。然而，淋巴细胞S1P1促进流出的机制以及CD69介导的S1P1调节模式仍不清楚。该提案将通过三个具体目标解决淋巴细胞出口的细胞和分子要求以及与出口调节相关的机制。第一个目标将结合使用细胞和多光子成像方法来表征淋巴细胞从淋巴结流出的 S1P1 依赖性步骤。目标 2 将重点确定 CD69 介导的 S1P1 功能和淋巴细胞排出抑制的机制。最终目标将使用遗传方法来识别淋巴细胞流出所需的其他分子。这一目标将建立在与澳大利亚克里斯托弗·古德诺（Christopher Goodnow）合作的基础上，以识别和表征表现出淋巴细胞运输改变的突变小鼠品系。作为这项工作的一部分，我们将精细绘制并描述导致 Cataract Shionogi (CTS) 小鼠胸腺出口缺陷的基因座。通过这些研究获得的信息应该为免疫调节分子的开发指明新的靶点。