Signaling Mechanisms for Leukocyte Migration Regulation

描述（由申请人提供）：定向细胞迁移、趋化性是白细胞浸润、募集、运输和归巢的基础，其不仅是正常免疫应答所需的，而且是许多炎症相关疾病（包括缺血再灌注、动脉粥样硬化、哮喘和败血症）的原因。此外，细胞迁移发生在胚胎发育、伤口愈合和肿瘤转移中。我们的长期目标是以小鼠原代中性粒细胞为模型细胞，了解趋化因子调节白细胞趋化性的信号转导机制及其在炎症相关疾病模型中的作用。本研究的中心假设是，多种信号通路可能共同发挥作用，以调节中性粒细胞的极化和方向性。本申请的目标是充分表征两种新的信号传导机制，并阐明这些信号传导途径如何调节体外中性粒细胞趋化性和体内招募。我们将使用分子和细胞生物学，生物化学，转基因，蛋白质组学，功能基因组学和先进的体外和体内成像方法的组合，以实现以下具体目标：1）为了阐明cofilin磷酸化的新信号机制，这是一个强调肌动蛋白重塑的事件，通过PLC和PI3K在中性粒细胞中的化学引诱物调节，以及信号传导机制在调节中性粒细胞极化和方向性中的作用。2)目的探讨整合素信号通路对PIP5K1C极化的调控机制，PIP5K1C在调节中性粒细胞趋化性及与内皮细胞的相互作用中具有重要作用。3)探讨这些趋化因子信号通路及其相互作用在中性粒细胞体外趋化和体内募集中的作用。

DESCRIPTION (provided by applicant): Directional cell migration, chemotaxis, underlies leukocyte infiltration, recruitment, trafficking and homing, which are not only required for normal immune responses, but also responsible for many inflammation-related diseases including ischemic reperfusion, atherosclerosis, asthma, and sepsis. In addition, cell migration occurs in embryonic development, wound healing, and tumor metastasis. Our long term goal is to understand the signaling mechanisms by which chemoattractants regulate leukocyte chemotaxis and their roles in inflammation-related diseases models with the mouse primary neutrophil as the model cell. The central hypothesis of this study is that multiple signaling pathways may function together to regulate neutrophil polarization and directionality. The goals of this application are to fully characterize two new signaling mechanisms and elucidate how these signaling pathways regulate neutrophil chemotaxis in vitro and recruitment in vivo. We will use a combination of molecular and cell biological, biochemical, transgenic, proteomic, functional genomic and advanced in vitro and in vivo imaging approaches to accomplish the following specific aims: 1) To elucidate the novel signaling mechanisms by which cofilin phosphorylation, an event underlining actin remodeling, is regulated by chemoattractants via PLC and PI3K in neutrophils and the role of the signaling mechanism in regulating neutrophil polarization and directionality. 2) To investigate the mechanisms by which integrin signaling regulates PIP5K1C polarization, that has important roles in regulating neutrophil chemotaxis and interaction with endothelial cells. 3) To investigate the roles of these chemoattractant signaling pathways and their interactions in neutrophil chemotaxis in vitro and recruitment in vivo.