ENDOTHELIAL CELL BIOLOGY IN INFLAMMATION

炎症中的内皮细胞生物学

• 批准号: 6848730
• 负责人: EUGENE C BUTCHER
• 金额: $ 32.96万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6848730
• 关键词: ENDOTHELIAL; CELL; BIOLOGY; INFLAMMATION

EXCEED THE SPACE PROVIDED. This proposal targets endothelial cell (EC) biology in leukocyte trafficking and inflammation, focusing on the role of vascular adhesion receptors and activating factors in the control of lymphocyte homing. We have shown that vascular signaling through Goci protein-linked receptors triggers integrin-dependent lymphocyte arrest in high endothelial venules in lymph nodes and Peyer's patches. Here we shall explore the hypothesis that vascular triggering of lymphocyte integrins is mediated by the emerging family of chemoattractant cytokines. and that these chemokines help control lymphocyte-EC recognition and hence lymphocyte recruitment in a site, inflammatory state, and lymphocyte subset-selective fashion. 1)The ability of novel chemokines to induce rapid ICAM-dependent adhesion of blood-borne naive and memory lymphocyte subsets, and to trigger their arrest under physiologic shear will be explored. Responding lymphocyte subsets will be identified by patterns of differentiation antigen, cytokine, and especially homing receptor expression. 2) We shall explore the hypothesis that chemokines can differentially activate lymphocyte ft2 vs. a4 integrins. thus providing a novel level of vascular control of leukocyte adhesion and recruitment. 3) The involvement of proadhesive chemokines in EC- triggered lymphocyte adhesion and arrest will be assessed in physiologic models. Antibodies to target chemokines will be used a) to assess in immunohistologic studies their display by vascular endothelium, and hence their availability for participation in physiologic adhesion-triggering responses; and b) to explore their physiologic importance in in vivo homing and in situ videomicroscopic studies of lymphocyte-EC interactions. We shall focus initially on hypothesized involvement of high endothelial venule-associated 6Ckine and/or MIP3$ in lymphocyte homing to secondary lymphoid tissues in vivo. 4) Receptor(s) for chemokines implicated in vascular arrest of lymphocytes will be identified, and antibodies against them will be used to characterize their involvement in endothelial interactions and lymphocyte homing into lymphoid tissues and/or sites of inflammation. Finally, in a continuation of earlier Aims, we shall 5) evaluate the phenotype of MAdCAM-1- deficient mice. The proposed studies should expand our understanding of the critical role of the vascular endothelium in regulating lymphocyte trafficking during normal and pathologic immune responses. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。 该提案针对白细胞运输和炎症中的内皮细胞（EC）生物学，重点关注血管粘附受体和激活因子在控制淋巴细胞归巢中的作用。我们已经表明，通过Goci蛋白连接受体的血管信号触发整合素依赖性淋巴细胞阻滞在淋巴结和派尔集合淋巴结的高内皮微静脉。在这里，我们将探讨的假设，血管触发淋巴细胞整合素介导的新兴家族的趋化细胞因子。并且这些趋化因子有助于控制淋巴细胞-EC识别，从而以部位、炎症状态和淋巴细胞亚群选择性方式控制淋巴细胞募集。1)将探索新型趋化因子诱导血源性幼稚和记忆淋巴细胞亚群的快速ICAM依赖性粘附，并在生理剪切下触发其停滞的能力。应答淋巴细胞亚群将通过分化抗原、细胞因子，特别是归巢受体表达的模式来鉴定。2)我们将探讨这一假说，即趋化因子可以差异激活淋巴细胞ft 2与α 4整合素。从而提供了白细胞粘附和募集的血管控制的新水平。3)将在生理模型中评估促粘附趋化因子在EC触发的淋巴细胞粘附和停滞中的参与。靶向趋化因子的抗体将用于a）在免疫组织学研究中评估其通过血管内皮的展示，从而评估其参与生理性粘连触发反应的可用性;和B）探索其在淋巴细胞-EC相互作用的体内归巢和原位视频显微镜研究中的生理重要性。我们将首先集中在假设参与高内皮微静脉相关的6Ckine和/或MIP 3 $在淋巴细胞归巢到次级淋巴组织在体内。4)将鉴定涉及淋巴细胞血管阻滞的趋化因子的受体，并将使用针对它们的抗体来表征它们参与内皮相互作用和淋巴细胞归巢到淋巴组织和/或炎症部位。最后，作为早期目标的延续，我们将评估MAdCAM-1缺陷小鼠的表型。 拟议的研究应扩大我们的理解，在正常和病理性免疫反应中，血管内皮细胞在调节淋巴细胞运输的关键作用。性能现场=