ENDOTHELIAL CELL BIOLOGY IN INFLAMMATION

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，重点是血管粘连的作用 受体和激活因子在控制淋巴细胞归巢。 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阻滞 淋巴结和派尔集合淋巴结中的内皮微静脉。的假设 淋巴细胞整合素的血管触发是由 新出现的趋化因子家族，这些趋化因子 有助于控制淋巴细胞-EC识别并因此控制淋巴细胞募集 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ICAM-1依赖性细胞凋亡的能力 粘附的血源性幼稚和记忆淋巴细胞亚群，并 将探索在生理剪切下触发它们的停滞。 应答淋巴细胞亚群将通过以下模式进行鉴定： 分化抗原，细胞因子，特别是归巢受体 表情2)研究人员将探讨以下假设： 趋化因子可以不同地激活淋巴细胞β 2与α 4 整合素，从而提供了一种新的白细胞血管控制水平 粘附和募集。3)促粘附趋化因子的参与 在EC触发的淋巴细胞粘附和阻滞中， 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在血管 内皮细胞，因此它们参与 生理性粘连触发反应;和B）探索其 在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。他将首先专注于 假设高内皮微静脉相关6 Ckine参与 和/或MIP 3 β在淋巴细胞归巢到次级淋巴组织中的作用 vivo. 4)参与血管阻滞的趋化因子受体 将识别淋巴细胞，并使用针对它们的抗体。 以表征其参与内皮相互作用， 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，他将评估 MAdCAM-1缺陷小鼠的表型。拟议的研究应扩大 我们对血管内皮细胞的关键作用的理解， 在正常和病理免疫过程中调节淋巴细胞运输 应答

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.