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，以及特定的挑战主题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脏、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中起着至关重要的作用，这一过程受到高度调节以确保组织稳态。100多年来，人们一直在研究血细胞的迁移及其与脉管系统细胞的相互作用，从简单生物体的显微镜检查，到复杂的生化和遗传学研究，再到活体哺乳动物炎症期间免疫细胞的高分辨率成像。这些研究提供了对炎症机制的深刻理解，并使炎症和免疫疾病的新疗法得以发展。然而，我们对维持组织稳态的机制以及在没有炎症的情况下免疫细胞是否被主动排除在非炎症组织之外的知识是不完整的。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存在缺陷知之甚少。我们的实验室和其他人最近的工作使我们假设，“负引导线索”使细胞迁移失活性或介导细胞排斥，例如在发育中的神经系统中描述的那些，也被内皮细胞用来阻止组织中免疫细胞的不适当募集和/或积累。在我们的初步数据中，我们发现代表性的引导分子在体外抑制白细胞迁移，在体内由非炎症内皮细胞表达，阻止白细胞附着和招募到组织。然而，在细胞应激或暴露于炎症细胞因子后，表达减少，降低了这些炎症细胞募集的障碍。我们相信这些数据代表了白细胞内皮相互作用的新范式。在这项拨款申请中，我们建议建立这些引导分子在白细胞和内皮细胞相互作用中的作用，并确定介导排斥和吸引相互作用的引导分子和受体对。这些研究将增加我们对血管和其他组织中炎症细胞募集、保留和退出的机制的理解，并将为调节白细胞积累提供潜在的治疗靶点。

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.