ENDOTHELIAL CELL BIOLOGY IN INFLAMMATION

说明(改编自《调查者摘要》)： 这项建议针对白细胞中的内皮细胞(EC)生物学 贩运和炎症，侧重于血管粘连的作用 淋巴细胞归巢调控中的受体和激活因子。 我们已经证明，通过Galphai蛋白连接的血管信号 受体在高水平触发整合素依赖的淋巴细胞停滞 淋巴结和Peyer‘s斑内有内皮小静脉。假说 淋巴细胞整合素的血管触发是由 新出现的趋化细胞因子家族，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 在一个部位，炎症状态，和淋巴细胞亚群选择性方式。 1)新型趋化因子快速诱导ICAM依赖的能力 血源性幼稚淋巴细胞亚群和记忆淋巴细胞亚群的黏附 将探讨在生理剪切力下触发他们的逮捕。 应答的淋巴细胞亚群将通过以下模式来识别 分化抗原、细胞因子，特别是归巢受体 表情。2)调查者将探索这样的假设 趋化因子可以不同地激活淋巴细胞β2和α4 整合素，从而提供了一种新的白细胞血管控制水平 附着性和招募。3)前黏附趋化因子的参与 在EC触发的淋巴细胞黏附和抑制中，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在血管中的表现 内皮细胞，因此它们可用于参与 生理黏附-触发反应；以及b)探索其 体内归巢和原位视频显微镜的生理学意义 淋巴细胞与内皮细胞相互作用的研究。他最初将把重点放在 高内皮微静脉相关6Ckine参与的假说 和/或MIP3β在淋巴细胞归巢至次级淋巴组织中的作用 活着。4)参与血管停滞的趋化因子受体(S) 淋巴细胞将被识别，并将使用针对它们的抗体 以确定它们参与内皮细胞相互作用的特征 淋巴细胞归巢到淋巴组织和/或炎症部位。 最后，为了延续先前的目标，他将评估 MAdCAM-1基因缺陷小鼠的表型。拟议的研究应扩大 我们对血管内皮细胞在心血管疾病中的关键作用的认识 调节正常和病理性免疫过程中的淋巴细胞转运 回应。

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.