Molecular Interactions of Myeloid Cells with Endothelium

这个项目广泛的长期目标是定义髓系之间相互作用的机制 白细胞、内皮细胞和血小板激活分子通路，调节细胞功能和 表型，这些功能如何变得失调，以及如何失调的相互作用和活动 导致炎症性血管和组织损伤。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-细胞相互作用的失调是人类主要综合征的主要特征，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。在最初 描述髓系白细胞拴系和黏附的关键机制，这个项目的工作有 重点关注这些黏附通路和炎症受体如何传递由外向内的信号 导致基因表达的改变。在上一个资助阶段，我们探索了转录后机制 基因调控，在人类生物学和后基因组时代的疾病中具有进化意义的问题， 并确定了关键信使RNA(MRNAs)的信号依赖翻译途径 髓系白细胞、内皮细胞和血小板以前未被识别并具有生理功能 意义。目前的应用建立在这些发现的基础上，并将表征新的信号- 依赖的翻译途径和基因基于翻译控制和基因的中心假设 信号依赖的翻译机制调节关键的先天免疫细胞表型、功能和 对急性和慢性炎症的反应。具体目标是：1)表征炎症性 调节髓系白细胞中mTOR翻译控制通路的机制；2)定义新的 MTOR在特殊的天然免疫效应细胞中的炎症活性；3)表征新的信号- 髓系白细胞中依赖的翻译机制；4)检验翻译- 髓系白细胞中受调控的基因包括一组转录子，这些转录子编码临界炎症 蛋白质，并可通过它们与多聚核糖体的结合来鉴定。这些研究将解决关键的差距 在我们对炎症系统的基因调控的知识中，有直接的临床相关性，并且是 创新是因为他们探索了新的概念和范式。

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.