MOLECULAR INTERACTIONS--MYELOID CELLS W ENDOTHELIUM

该项目的长期目标是了解粘合剂 相互作用诱导并整合细胞间信号传导， 单核细胞和嗜中性粒细胞，它们是髓系的白细胞， 和内皮细胞。我们还将确定这些相互作用 影响随后的白细胞功能反应， 炎症和炎性疾病。标题的改变 “神经细胞粘附于内皮细胞的分子机制”项目 “髓样细胞与内皮细胞的分子相互作用”反映了一个 更大的范围，包括对粘附依赖性信号机制的关注 以及单核细胞与内皮细胞相互作用的新研究， 除了对PMNs的研究。特异性粘附分子系链 内皮细胞和骨髓细胞在一起;类似地，这种束缚 分子可以将血小板与骨髓细胞结合， 髓系白细胞之间的联系我们将确定这些 粘附相互作用导致细胞内信号的产生， 改变骨髓细胞的重要炎症功能。我们将重点 对即刻早期基因的表达、对细胞铺展以及对相关的 细胞反应。我们将确定已知的分子是如何 髓系白细胞传递信号，并在作用于 与其他因素的配合。使用分离的髓系白细胞和培养的 内皮，转染细胞，模型膜和纯化的分子，我们 将在具体目标1和2中描述选择素的作用。在 具体目标3，我们将使用类似的策略来识别网络共享， ICAM-3是ICAM家族的一个新成员， 骨髓细胞相互作用。在具体目标4中，我们将研究“由外而内” 骨髓细胞中β 32（CD 11/CD 18）整合素的信号传导 传统的方法，白细胞与特定配体的粘附， 与可能诱导功能改变的抗体孵育，以及 新的方法-研究具有靶向缺失的髓样细胞 单个CD 11/CD 18异二聚体。来自这些简化系统的信息 然后将用于分析复杂的炎症模型（细胞-细胞 体外相互作用），并最终确定新的策略， 了解和改变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.