MOLECULAR INTERACTIONS--MYELOID CELLS W ENDOTHELIUM

这个项目的长期目标是了解粘合剂是如何 相互作用诱导和整合细胞间信号转导 单核细胞和中性粒细胞，这是髓系的白细胞， 和内皮细胞。我们还将确定这些交互如何 动态平衡对白细胞后续功能反应的影响 炎症和炎症性疾病。《纽约时报》标题的更改 中性粒细胞与血管内皮细胞黏附的分子机制 “髓系细胞与内皮细胞的分子相互作用”反映了一种 更大的范围，包括关注黏附依赖的信号机制 以及单核细胞与内皮细胞相互作用的新研究， 除了对PMN的研究之外。特异性黏附分子系绳 内皮细胞和髓系细胞结合在一起；类似地，这种拴系 分子能将血小板与髓系细胞结合，并能调节黏附。 在髓系白细胞之间。我们将确定这些 粘附性相互作用导致细胞内信号的产生 改变髓系细胞的关键炎症功能。我们将专注于 即刻早期基因的表达与细胞扩散及相关 细胞反应。我们将确定已知的分子是如何系住的 髓系白细胞传递信号，并在行动时协调它们 与其他因素协调一致。用分离的髓系白细胞培养 血管内皮细胞、转基因细胞、模型膜和纯化分子 将表征选择素的作用，具体针对L和2。 具体目标3，我们将使用类似的策略来确定系留和 细胞间黏附分子家族新成员细胞间黏附分子-3的信号机制 髓系细胞的相互作用。在具体目标4中，我们将考察“由外而内” β32(CD11/CD18)整合素在髓系细胞中的信号转导 传统的方法，白细胞与特定配体的黏附和 与可能导致功能改变的抗体孵育，以及 一种新的方法--靶向缺失的髓系细胞研究 单个CD11/CD18异源二聚体。来自这些精简系统的信息 将被用来分析复杂的炎症模型(细胞-细胞 体外相互作用)，并最终确定新的治疗策略 了解和修改体内和人体内的炎症事件。

The long term goal of this project is to understand how adhesive interactions induce and integrate intercellular signaling between monocytes and neutrophils, which are leukocytes of the myeloid lineage, and endothelial cells. We also will determine how these interactions influence subsequent functional responses of the leukocytes in homeostatic inflammation and in inflammatory disease. The change in title of the project from "Molecular Mechanisms of Neutrophil Adhesion to Endothelium" to "Molecular Interactions of Myeloid Cells with Endothelium" reflects a larger scope, including a focus on adhesion-dependent signaling mechanisms and new investigations of the interactions of monocytes with endothelium, in addition to studies of PMNs. Specific adhesion molecules tether endothelial cells and myeloid cells together; similarly, such tethering molecules can bind platelets to myeloid cells and can mediate adhesion between the myeloid leukocytes themselves. We will determine how these adhesive interactions lead to the generation of intracellular signals that alter critical inflammatory functions of the myeloid cells. We will focus on expression of immediate-early genes, on cell spreading, and on related cellular responses. We will determine how molecules known to tether myeloid leukocytes transmit signals, and orchestrate them when acting in concert with other factors. Using isolated myeloid leukocytes and cultured endothelium, transfected cells, model membranes and purified molecules, we will characterize the roles of selectins, in Specific Aims l and 2. In Specific Aim 3, we will use similar strategies to identify tethering and signaling mechanisms of ICAM-3, a new member of the ICAM family, in myeloid cell interactions. In Specific Aim 4, we will examine "outside-in" signaling by beta32 (CD11/CD18) integrins in myeloid cells using two traditional approaches, adhesion of leukocytes to specific ligands and incubation with antibodies that may induce functional alterations, and a novel approach - study of myeloid cells with targeted deletions of individual CD11/CD18 heterodimers. Information from these reduced systems will then be used to analyze complex models of inflammation (cell-cell interactions in vitro) and, ultimately, to identify new strategies for understanding and modifying inflammatory events in vivo and in humans.