MOLECULAR INTERACTIONS--MYELOID CELLS W ENDOTHELIUM

分子相互作用——骨髓细胞内皮

• 批准号: 6536975
• 负责人: Guy A. Zimmerman
• 金额: $ 30.95万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536975
• 关键词: CD antigens; atherosclerosis; biological signal transduction; cell cell interaction; dimer; gene expression; glycoproteins; homeostasis; human tissue; inflammation; integrins; laboratory rabbit; leukocyte adhesion molecules; membrane proteins; molecular biology; monocyte; neutrophil; polymerase chain reaction; protein purification; selectins; tissue /cell culture; transfection; vascular endothelium

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.

该项目的长期目标是了解粘合剂如何 相互作用诱导和整合细胞间信号传导 单核细胞和中性粒细胞，它们是骨髓谱系的白细胞， 和内皮细胞。我们还将确定这些相互作用如何 影响白细胞随后的稳态功能反应 炎症和炎症性疾病。标题的变更 项目来自“中性粒细胞粘附内皮细胞的分子机制” “骨髓细胞与内皮细胞的分子相互作用”反映了 范围更大，包括关注粘附依赖性信号机制 以及单核细胞与内皮细胞相互作用的新研究， 除了 PMN 的研究之外。特异性粘附分子系链 内皮细胞和骨髓细胞在一起；同样，这种束缚 分子可以将血小板与骨髓细胞结合并可以介导粘附 髓系白细胞本身之间。我们将确定如何这些 粘附相互作用导致细胞内信号的产生 改变骨髓细胞的关键炎症功能。我们将重点 立即早期基因的表达、细胞扩散以及相关的 细胞反应。我们将确定分子如何束缚 髓系白细胞传递信号，并在作用时协调它们 与其他因素相协调。使用分离的骨髓白细胞并培养 内皮、转染细胞、模型膜和纯化分子，我们 将在具体目标 l 和 2 中描述选择素的作用。 具体目标 3，我们将使用类似的策略来识别网络共享和 ICAM家族新成员ICAM-3的信号传导机制 骨髓细胞相互作用。在具体目标 4 中，我们将研究“由外向内” 使用两种方法在骨髓细胞中通过 beta32 (CD11/CD18) 整合素发出信号 传统方法，白细胞与特定配体的粘附和 与可能诱导功能改变的抗体一起孵育，以及 新方法 - 通过靶向删除骨髓细胞的研究 单个 CD11/CD18 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类的炎症事件。