Signaling Mechanisms for Leukocyte Migration Regulation

描述(申请人提供)：定向细胞迁移，趋化，是白细胞渗透，招募，运输和归巢的基础，这不仅是正常免疫反应所必需的，也是许多炎症相关疾病的罪魁祸首，包括缺血再灌注、动脉粥样硬化、哮喘和败血症。此外，细胞迁移发生在胚胎发育、伤口愈合和肿瘤转移过程中。我们的长期目标是了解趋化物质调节白细胞趋化的信号机制，以及它们在以小鼠原代中性粒细胞为模型细胞的炎症相关疾病模型中的作用。这项研究的中心假设是，多个信号通路可能共同调节中性粒细胞的极化和方向性。这项应用的目的是充分描述两种新的信号机制，并阐明这些信号通路如何在体外和体内调节中性粒细胞的趋化和募集。我们将结合分子和细胞生物学、生化、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来实现以下特定目标：1)阐明趋化剂通过PLC和PI3K在中性粒细胞中调节肌动蛋白磷酸化的新的信号机制，以及该信号机制在调节中性粒细胞极化和方向性中的作用。2)探讨整合素信号调节PIP5K1C极化的机制，该信号在调节中性粒细胞趋化及与内皮细胞的相互作用中具有重要作用。3)探讨这些趋化信号通路在中性粒细胞体外趋化和体内募集中的作用及其相互作用。 与公共卫生相关：细胞迁移是从胚胎发育到免疫反应的许多生物学过程的基础。它在导致许多人类疾病的炎症中也发挥着重要作用。细胞的定向迁移受化学诱导剂的调控。这项研究计划是为了了解趋化物质激活的各种信号通路如何调控细胞定向迁移。这项研究可能不会阐明这一基本生物过程是如何调控的，但也可能为治疗与炎症相关的人类疾病提供潜在的治疗目标。

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. PUBLIC HEALTH RELEVANCE: Cell migration underlies many of biological processes that range from embryonic development to immune responses. It also plays important roles in inflammation that underlies many human diseases. Directional cell migration is regulated by chemoattractants. This research proposal is to understand how directional cell migration is regulated by various signaling pathways activated by chemoattractants. The study may not shed lights into how this fundamental biological process is regulated, but may also provide potential therapeutic targets for treating inflammation-related human diseases.