ENDOTHELIAL CELL BIOLOGY IN INFLAMMATION

炎症中的内皮细胞生物学

• 批准号: 6138407
• 负责人: EUGENE C BUTCHER
• 金额: $ 27.65万
• 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 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138407
• 关键词: biological signal transduction; cell adhesion molecules; cell biology; chemokine; cytokine; human tissue; inflammation; integrins; laboratory mouse; leukocyte activation /transformation; lymphocyte; receptor expression; vascular endothelium; video microscopy

DESCRIPTION (Adapted from Investigator's Abstract): 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 Galphai protein-linked receptors triggers integrin-dependent lymphocyte arrest in high endothelial venules in lymph nodes and Peyer's patches. The hypothesis is 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) The investigator will explore the hypothesis that chemokines can differentially activate lymphocyte beta2 vs. alpha4 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. He will focus initially on hypothesized involvement of high endothelial venule-associated 6Ckine and/or MIP3beta 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, he will 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.

描述（改编自研究者摘要）： 该提案针对白细胞中的内皮细胞 (EC) 生物学 运输和炎症，重点关注血管粘附的作用 控制淋巴细胞归巢的受体和激活因子。 我们已经证明，通过 Galphai 蛋白连接的血管信号传导 受体触发整合素依赖性淋巴细胞停滞 淋巴结和派尔氏集结中的内皮小静脉。假设 淋巴细胞整合素的血管触发是由 新兴的趋化细胞因子家族，并且这些趋化因子 帮助控制淋巴细胞-EC 识别，从而控制淋巴细胞募集 以部位、炎症状态和淋巴细胞亚群选择性方式。 1) 新型趋化因子诱导快速 ICAM 依赖性的能力 血源性幼稚淋巴细胞和记忆淋巴细胞亚群的粘附，以及 将探讨在生理剪切下触发它们的逮捕。 反应淋巴细胞亚群将通过以下模式来识别： 分化抗原、细胞因子，尤其是归巢受体 表达。 2）研究者将探索以下假设： 趋化因子可以差异性地激活淋巴细胞 beta2 和 alpha4 整合素，从而提供新水平的白细胞血管控制 粘附和招募。 3）促粘附趋化因子的参与 EC 触发的淋巴细胞粘附和停滞将在 生理模型。靶向趋化因子的抗体将用于 a) 在免疫组织学研究中评估它们通过血管的表现 内皮细胞，因此它们参与的可用性 生理性粘附触发反应； b) 探索他们的 体内归巢和原位视频显微镜的生理重要性 淋巴细胞-EC相互作用的研究。他最初将重点关注 假设涉及高内皮微静脉相关 6Ckine 和/或MIP3beta在淋巴细胞归巢至次级淋巴组织中 体内。 4) 与血管停滞有关的趋化因子受体 将识别淋巴细胞，并使用针对它们的抗体 描述它们参与内皮相互作用的特征， 淋巴细胞归巢到淋巴组织和/或炎症部位。 最后，在先前目标的延续中，他将 5) 评估 MAdCAM-1 缺陷小鼠的表型。拟议的研究应扩大 我们对血管内皮的关键作用的理解 在正常和病理免疫过程中调节淋巴细胞运输 回应。