Immunomodulatory functions of neuronal guidance cues

描述(由申请人提供)：本申请涉及广泛的挑战领域(04)临床研究，以及特定挑战主题04-HL-103评估白细胞与血小板、红细胞和内皮细胞相互作用在心肺和血液疾病发病机制中的作用。细胞迁移在胚胎发育和炎症过程中起着至关重要的作用，这一过程受到高度调控，以确保组织的动态平衡。血细胞的迁移及其与血管系统细胞的相互作用的研究已经有100多年的历史，从简单生物的显微镜检查，到复杂的生化和遗传学研究，再到对免疫细胞的高分辨率成像，在活体哺乳动物的炎症过程中。这些研究提供了对炎症机制的极大了解，并使炎症和免疫疾病的新疗法得以开发。然而，我们对维持组织内环境平衡的机制以及免疫细胞是否在没有炎症的情况下被主动排除在非炎症组织之外的了解是不完整的。同样，我们对炎症消退过程中驱动白细胞退出的信号以及这一过程在慢性炎症条件下是否有缺陷也知之甚少。我们实验室和其他实验室最近的工作让我们假设，内皮细胞也会利用抑制细胞迁移或介导细胞排斥的“负面指导信号”，例如发育中的神经系统中描述的那些信号，来阻止免疫细胞在组织中的不适当招募和/或积累。在我们的初步数据中，我们发现具有代表性的引导分子在体外抑制白细胞的迁移，由非炎症内皮细胞表达，并防止白细胞在体内附着和募集到组织中。然而，在细胞应激或暴露于炎性细胞因子后，表达减少，从而降低了炎性细胞募集的这些障碍。我们认为，这些数据代表了白细胞的一个新范式：内皮相互作用。在这项拨款申请中，我们建议确定这些引导分子在白细胞：内皮细胞相互作用中的作用，并确定引导分子：介导排斥和吸引相互作用的受体对。这些研究将加深我们对导致炎症细胞在血管和其他组织中募集、保留和退出的机制的理解，并将为调节白细胞聚集提供潜在的治疗靶点。 公共卫生相关性：细胞迁移在胚胎发育和炎症过程中起着至关重要的作用，这一过程受到高度调控，以确保组织的动态平衡。在这项挑战拨款中，我们建议建立炎性细胞运输的新范式，识别神经元引导分子：介导白细胞与血管内皮细胞排斥和吸引相互作用的受体对。

DESCRIPTION (provided by applicant): This application addresses broad Challenge area (04) Clinical research, and specific Challenge Topic 04-HL-103 Assess the role of leukocyte interaction with platelets, erythrocytes, and endothelium in the pathogenesis of heart, lung, and blood diseases. Cell migration plays essential roles in embryonic development and inflammation, and this process is highly regulated to ensure tissue homeostasis. The migration of blood cells and their interactions with the cells of the vasculature, have been studied for over 100 years, from microscopic examination of simple organisms, through complex biochemical and genetic studies, to high resolution imaging of immune cells in during inflammation in living mammals. These studies have provided a great understanding of the mechanisms of inflammation and have allowed the development of new therapeutics for inflammatory and immune disorders. However our knowledge of the mechanisms by which tissue homeostasis is maintained and whether immune cells are actively excluded from non-inflamed tissues in the absence of inflammation is incomplete. Similarly, we have little understanding of the signals that can drive leukocyte exit during resolution of inflammation and whether this process is defective in chronic inflammatory conditions. Recent work from our lab and others has led us to hypothesize that 'negative guidance cues' which inactivate cell migration or mediate cell repulsion, such as those described in the developing nervous system, are also employed by endothelial cells to impede inappropriate recruitment and/or accumulation of immune cells in tissues. In our preliminary data we have found that representative guidance molecules inhibit leukocyte migration in vitro, are expressed by non-inflamed endothelial cells and prevent leukocyte attachment and recruitment to tissues in vivo. However, under cell stress or following exposure to inflammatory cytokines, expression is reduced, lowering these barriers for inflammatory cell recruitment. We believe that these data represent a new paradigm for leukocyte: endothelial interactions. In this grant application, we propose to establish the role of these guidance molecules in leukocyte: endothelial cell interactions, and identify guidance molecule: receptor pairs that mediate repulsive and attractive interactions. These studies will increase our understanding of the mechanisms that lead to recruitment, retention, and exit of inflammatory cells in the vasculature and other tissues in and will provide potential therapeutic targets for modulation of leukocyte accumulation. PUBLIC HEALTH RELEVANCE: Cell migration plays essential roles in embryonic development and inflammation, and this process is highly regulated to ensure tissue homeostasis. In this challenge grant, we propose to establish a new paradigm for inflammatory cell trafficking, identifying neuronal guidance molecule: receptor pairs that mediate repulsive and attractive interactions of leukocytes with vascular endothelium.