Beyond PECAM: Mechanisms of Transendothelial Migration

超越 PECAM：跨内皮迁移机制

• 批准号: 8284380
• 负责人: William A Muller
• 金额: $ 40.96万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284380
• 关键词: Acute; Area; Asthma; Atherosclerosis; Autoimmune Diseases; Award; Blocking Antibodies; Blood Cells; Blood Circulation; Cell Adhesion Molecules; Cell Line; Cells; Chronic; Complement; Data; Disease; Drug or chemical Tissue Distribution; Endothelial Cells; Endothelium; Funding; Future; Goals; Graft Rejection; Grant; Human; Immigration; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Instruction; Intercellular adhesion molecule 1; Knowledge; Lateral; Lead; Leukocytes; Membrane; Membrane Protein Traffic; Microtubules; Modeling; Molecular; Monoclonal Antibodies; Mus; Phosphorylation; Play; Process; Recruitment Activity; Recycling; Reporting; Research; Rheumatoid Arthritis; Role; Septic Shock; Signal Transduction; Site; Surface; Techniques; Therapeutic; Time; Tissues; Tyrosine; White Blood Cell Count procedure; Wild Type Mouse; Work; Wound Healing; base; fighting; in vitro Model; in vivo; intravital microscopy; microorganism; migration; monocyte; neutrophil; postcapillary venule; response; trafficking

PROJECT SUIVIMARY (See instructions): The long-term objectives of this research application is to better understand the cellular and molecular basis of the inflammatory response in order to develop better therapies to augment it in conditions where the host's immune response is compromised, and to inhibit it under conditions where the response is counterproductive, such as in inflammatory diseases like atherosclerosis, rheumatoid arthritis and other autoimmune diseases, septic shock, asthma, and transplant rejection. A critical step in the inflammatory response is the migration of leukocytes out ofthe bloodstream to the site of inflammation. We have been studying the molecules and mechanisms responsible for diapedesis-the step in this process in which leukocytes pass across the endothelial cells lining postcapillary venules at sites of leukocyte egress. In the first funding period of this grant, we discovered a molecule (CD99) and a mechanism (targeted recycling of membrane from an intemal perijunctional compartment called the LBRC) that play significant roles in diapedesis. In the second funding period thus far (i.e., the first 3.5 years ofthe MERIT award) we have already accomplished most of the Specific Aims of the 5 year plane: We have investigated how CD99 regulates diapedesis. We have discovered that it is present in the LBRC and its function requires the presence of PECAM in the compartment as well. We have cloned the mouse version of CD99 and the related molecule CD99L2 and demonstrated that both play a role in transmigration. We have demonstrated that transcellular migration involves the same mechanism as paracellular migration: Targeted membrane trafficking from the LBRC to the site of migration in a microtubule-dependent manner. The goals for the MERIT extension period are to develop the work proposed for these specific aims to answer the next important questions. These include: What signals from CD99 are required to complete transmigration? Why does CD99 function depend on PECAM? (How do these molecules interact?) Do CD99 and CD99L2 complement each other's function in vivo? If so, how? Is blocking them therapeutic in models of chronic inflammatory disease? How is LBRC membrane recruited for transcellular migration in vitro and in vivo?

项目随附资料（见说明）： 这项研究应用的长期目标是更好地了解细胞和分子基础 为了开发更好的治疗方法，以增加它的条件下， 宿主的免疫反应受到损害，并在反应受到损害的条件下抑制它。 相反，如在炎性疾病，如动脉粥样硬化，类风湿性关节炎和其他 自身免疫性疾病、感染性休克、哮喘和移植排斥。在这场煽动性的 反应是白细胞从血流中迁移到炎症部位。我们一直 研究导致腹膜粘连的分子和机制--这一过程中的一步， 在白细胞排出的部位，白细胞穿过毛细血管后小静脉的内皮细胞。在 在这项资助的第一个资助期内，我们发现了一种分子（CD 99）和一种机制（有针对性地回收 来自称为LBRC的内膜周连接区室的膜），其在以下方面发挥重要作用： 渗出到目前为止，在第二个供资期（即，第一个3.5年的MERIT奖），我们有 已经完成了5年飞机的大部分具体目标：我们已经研究了CD 99如何 调节渗出。我们发现它存在于LBRC中，其功能需要 在隔室中也存在PECAM。我们已经克隆了小鼠CD 99， 相关分子CD 99 L2，并证明两者都在迁移中发挥作用。我们已经证明 跨细胞迁移涉及与细胞旁迁移相同的机制：靶向膜 以微管依赖性方式从LBRC运输到迁移位点。下组织生产的目标 MERIT扩展期的制定工作提出了针对这些具体目标的回答 重要的问题这些问题包括：需要CD 99的哪些信号才能完成穿越？ 为什么CD 99的功能依赖于PECAM？(How这些分子会相互作用吗？）做CD 99和CD 99 L2 在体内功能互补如果是，如何做到？在慢性炎症模型中， 炎症性疾病？LBRC膜如何在体外和体内被募集用于跨细胞迁移？