Molecular Interactions of Myeloid Cells with Endothelium

描述（由申请人提供）：本项目的广泛长期目标是确定髓系白细胞、内皮细胞和血小板之间的相互作用激活调节细胞功能和表型的分子途径的机制，这些功能如何失调，以及失调的相互作用和活动如何导致炎性血管和组织损伤。控制这些事件的分子机制和途径提供了基本的生物学见解;此外，它们与人类疾病直接相关，因为失调的炎性细胞-细胞相互作用是主要人类综合征的关键特征，这些综合征跨越从脓毒症的急性表现到动脉粥样硬化及其并发症的范围。在初步表征髓系白细胞束缚和粘附的关键机制后，该项目的工作集中在这些粘附途径和炎症受体传递的由外向内的信号如何导致基因表达改变。在上一个资助期间，我们探索了基因调控的转录后机制，这是后基因组时代人类生物学和疾病中一个不断发展的重要问题，并确定了髓系白细胞，内皮细胞和血小板中关键信使RNA（mRNA）的信号依赖性翻译途径，这些途径以前未被识别并具有生理意义。本申请建立在这些发现的基础上，并将基于翻译控制和信号依赖性翻译机制调节急性和慢性炎症中的关键先天免疫细胞表型、功能和反应的中心假设来表征新的信号依赖性翻译途径和基因。具体目标是：1）表征在髓样白细胞中调节mTOR翻译控制途径的炎性机制; 2）定义mTOR在特化的先天免疫效应细胞中的新的炎性活性; 3）表征髓样白细胞中的新的信号依赖性翻译机制; 4）检验髓系白细胞中的转录调控基因包含亚转录调控基因的假设。编码关键炎症蛋白的转录物组，可通过与多核糖体的结合来鉴定。这些研究将解决我们对炎症系统基因调控知识的关键空白，具有直接的临床相关性，并且具有创新性，因为它们探索了新的概念和范式。

DESCRIPTION (provided by applicant): 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.