Molecular Interactions of Myeloid Cells with Endothelium

描述(申请人提供)：该项目广泛的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通路的机制，这些功能如何变得失调，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，因为失调的炎症细胞-细胞相互作用是人类主要综合征的关键特征，从脓毒症的急性表现到动脉粥样硬化及其并发症。在最初确定了髓系白细胞拴系和黏附的关键机制后，该项目的工作重点是这些黏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的变化。在上一个资助阶段，我们探索了基因调控的转录后机制，这是一个在人类生物学和后基因组时代疾病中具有进化意义的问题，并确定了髓系白细胞、内皮细胞和血小板中关键信使RNA(MRNAs)的信号依赖翻译途径，这些途径以前未被识别，具有生理意义。目前的应用建立在这些发现的基础上，并将基于翻译控制和信号依赖翻译机制调节急、慢性炎症中关键的先天免疫细胞表型、功能和反应的中心假设来表征新的信号依赖翻译途径和基因。其具体目的是：1)确定调节髓系白细胞中mTOR翻译控制途径的炎症机制；2)确定mTOR在特殊的先天免疫效应细胞中的新的炎症活性；3)表征髓系白细胞中新的信号依赖的翻译机制；4)检验这一假说，即髓系白细胞中受翻译调控的基因包括编码关键炎症蛋白的转录子组，并且可以通过它们与多聚核糖体的关联来识别。这些研究将解决我们在炎症系统中基因调控知识方面的关键空白，具有直接的临床意义，并具有创新性，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.