ENDOTHELIAL CELL BIOLOGY IN INFLAMMATION

超出所提供的空间。本研究的目标是内皮细胞（EC）生物学在白细胞运输和炎症中的作用，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，血管信号通过Goci蛋白连接受体触发整合素依赖性淋巴细胞阻滞在高内皮小静脉在淋巴结和Peyer's补丁。在这里，我们将探讨一种假设，即淋巴细胞整合素的血管触发是由新出现的趋化因子家族介导的。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的方式募集淋巴细胞。1)将探索新的趋化因子诱导血源性幼稚淋巴细胞和记忆淋巴细胞亚群的icam依赖性快速粘附，并在生理剪切下触发它们的抑制的能力。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识别。2)我们将探讨趋化因子对淋巴细胞ft2和a4整合素激活的差异假设。因此提供了一个新的水平的血管控制白细胞粘附和募集。3)前粘附趋化因子在EC触发的淋巴细胞粘附和阻滞中的作用将在生理模型中进行评估。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在血管内皮中的表现，从而评估其参与生理性粘附触发反应的可用性；b)探索它们在体内归巢和淋巴细胞- ec相互作用的原位视频显微镜研究中的生理学重要性。我们将首先关注高内皮小静脉相关的6Ckine和/或MIP3$参与体内淋巴细胞归巢到次级淋巴组织的假设。4)将鉴定与淋巴细胞血管阻滞有关的趋化因子受体，并使用针对它们的抗体来表征它们在内皮相互作用和淋巴细胞归巢到淋巴组织和/或炎症部位的参与。最后，在早期目的的延续中，我们将评估MAdCAM-1缺陷小鼠的表型。提出的研究应该扩大我们对血管内皮在正常和病理免疫反应中调节淋巴细胞运输的关键作用的理解。网站性能 ======================================== 节结束 ===========================================

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===========================================