Molecular Interactions of Myeloid Cells with Endothelium

骨髓细胞与内皮细胞的分子相互作用

• 批准号: 8053936
• 负责人: Guy A. Zimmerman
• 金额: $ 37.23万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053936
• 关键词: Acute; Address; Adhesions; Atherosclerosis; Binding; Blood Platelets; Blood Vessels; Cell Communication; Cell model; Cell physiology; Cells; Chronic; Code; Disease; Effector Cell; Endothelial Cells; Endothelium; Event; Funding; Gene Expression; Gene Expression Regulation; Genes; Genomics; Goals; Human; Human Biology; Immune; Inflammation; Inflammatory; Injury; Knowledge; Lead; Leukocytes; Messenger RNA; Molecular; Myelogenous; Myeloid Cells; Pathway interactions; Phenotype; Physiological; Polyribosomes; Productivity; Progress Reports; Proteins; Role; Sepsis; Signal Pathway; Signal Transduction; Subgroup; Syndrome; System; Testing; Tissues; Transcript; Translations; Work; base; clinically relevant; human FRAP1 protein; human disease; innovation; insight; novel; programs; receptor; response

The broad long-term goals of this project are to define mechanisms by which interactions between myeloid leukocytes, endothelial cells and platelets activate molecular pathways that regulate cellular function and phenotype, how these functions become dysregulated, and how dysregulated interactions and activities cause inflammatory vascular and tissue injury. Molecular mechanisms and pathways that control these events provide fundamental biologic insights; in addition, they are directly relevant to human disease, since dysregulated inflammatory cell-cell interactions are key features of major human syndromes that span a spectrum from the acute manifestations of sepsis to atherosclerosis and its complications. After initially characterizing key mechanisms of myeloid leukocyte tethering and adhesion, work in this project has focused on how outside-in signals delivered by these adhesion pathways and by inflammatory receptors lead to altered gene expression. In the last funding period we explored post-transcriptional mechanisms of gene regulation, an issue of evolving significance in human biology and disease in the post-genomic era, and have identified pathways for signal-dependent translation of critical messenger RNAs (mRNAs) in myeloid leukocytes, endothelial cells and platelets that were previously unrecognized and have physiologic significance. The current application builds on these discoveries, and will characterize novel signal- dependent translation pathways and genes based on the central hypothesis that translational control and signal-dependent translation mechanisms regulate key innate immune cell phenotypes, functions and responses in acute and chronic inflammation. The specific aims are: 1) to characterize inflammatory mechanisms that regulate the mTOR translational control pathway in myeloid leukocytes; 2) define new inflammatory activities of mTOR in specialized innate immune effector cells; 3) characterize novel signal- dependent translation mechanisms in myeloid leukocytes; 4) test the hypothesis that translationally- regulated genes in myeloid leukocytes comprise a sub-group of transcripts that code for critical inflammatory proteins and can be identified by their association with polyribosomes. The studies will resolve critical gaps in our knowledge of gene regulation in inflammatory systems, have direct clinical relevance, and are innovative because they explore new concepts and paradigms.

该项目的广泛长期目标是定义骨髓细胞之间相互作用的机制 白细胞、内皮细胞和血小板激活调节细胞功能的分子途径 表型，这些功能如何失调，以及相互作用和活动如何失调 引起血管和组织炎症损伤。控制这些的分子机制和途径 事件提供了基本的生物学见解；此外，它们与人类疾病直接相关，因为 炎症细胞间相互作用失调是人类主要综合征的关键特征，这些综合征跨越了 从脓毒症的急性表现到动脉粥样硬化及其并发症。最初之后 该项目的工作描述了骨髓白细胞束缚和粘附的关键机制 重点关注这些粘附途径和炎症受体如何传递由外而内的信号 导致基因表达改变。在上一个资助期间，我们探索了转录后机制 基因调控是后基因组时代人类生物学和疾病中不断发展的重要问题， 并确定了关键信使 RNA (mRNA) 信号依赖性翻译的途径 以前未被识别并具有生理学特征的髓系白细胞、内皮细胞和血小板 意义。当前的应用建立在这些发现的基础上，并将表征新颖的信号- 基于翻译控制和翻译控制的中心假设的依赖翻译途径和基因 信号依赖性翻译机制调节关键的先天免疫细胞表型、功能和 急性和慢性炎症反应。具体目标是：1）表征炎症 调节髓系白细胞中 mTOR 翻译控制通路的机制； 2）定义新的 mTOR 在专门的先天免疫效应细胞中的炎症活性； 3）表征新信号- 髓系白细胞中的依赖性翻译机制； 4）测试平移的假设- 骨髓白细胞中的调节基因包含编码关键炎症的转录子亚组 蛋白质，可以通过它们与多核糖体的结合来识别。这些研究将解决关键差距 根据我们对炎症系统基因调控的了解，具有直接的临床相关性，并且 创新是因为他们探索新的概念和范例。