SIGNAL TRANSDUCTION IN PMN AND EOSINOPHIL ACTIVATION

描述(申请人摘要)：该项目的长期目标是 为了确定人类中性粒细胞和嗜酸性粒细胞的信号通路 对炎症和过敏性挑战的反应。尽管功能性的 中性粒细胞对吞噬细胞攻击和趋化因子的反应 虽然已被广泛研究，但具体的刺激途径尚不清楚。 人们对中性粒细胞对细胞因子的反应知之甚少。然而， 响应吞噬细胞挑战和细胞因子的信号通路出现 变得与众不同。此外，人们对中国的信令系统知之甚少 嗜酸性粒细胞，因为它们很难分离。的一个基本目标 这个项目是为了确定中性粒细胞和嗜酸性粒细胞如何在 对于相同的炎症和过敏刺激，细胞类型有特定的方式。的 特别有趣的是细胞类型之间的相互作用，这些细胞类型有助于 过度活跃的反应。具体地说，我们将专注于唤起 刺激或启动其他细胞的产品。我们的目标是定义 受体刺激之间信号通路的中间步骤 以及胞浆磷脂酶A2的激活。的具体领域 感兴趣的是：1)磷脂酶对磷脂酰胆碱代谢的作用 中性粒细胞和嗜酸性粒细胞对变态反应的反应；2) 中性粒细胞和嗜酸性粒细胞刺激下的信号通路 对细胞因子(TNFa、GM-CSF)和趋化因子(PAF、C5a、 5-羟基二十碳四烯酸和5-氧代-15(OH)二十碳四烯酸)。我们的 初步研究导致假设磷脂酶D产物是 Raf-1和丝裂原激活蛋白的调节所需 激活素通路。因此，上述对这些系统的刺激 提到的细胞因子和趋化因子将是该项目的重点。 为了实现这些总体目标，我们将追求以下具体目标 目的：1)确定磷脂酶D在中性粒细胞和 嗜酸性粒细胞信号通路；2)确定 中性粒细胞和嗜酸性粒细胞对刺激的反应。总体而言，这个项目 将提供对细胞功能控制的进一步理解。 对过敏刺激的反应和确定药理靶点 治疗。可以预见，多个信号对 完全过敏反应，没有一种介体可以作为靶点 成功地改善了疾病结局。因此，多个战略的 可能需要进行干预。我们对细胞间相互作用的研究 类型和调解人将为这些战略提供基础。

DESCRIPTION (Applicant's abstract): The long term goal of this program is to define the signalling pathways of human neutrophils and eosinophils in response to inflammatory and allergic challenge. Although the functional response of neutrophils to phagocytic challenge and chemotactic factors has been studied extensively, the stimulatory pathways are not known in detail. Less is known about the responses of neutrophils to cytokines. However, the signalling pathways in response to phagocytic challenge and cytokines appear to be different. Moreover, little is known of the signalling systems in eosinophils because they have been difficult to isolate. A basic goal of this project is to determine how neutrophils and eosinophils respond in a cell type specific manner to the same inflammatory and allergic stimuli. Of special interest is the interaction among cell types which contribute to the hyperactive response. Specifically, we will focus on stimuli which evoke products either stimulating or priming other cells. Our goal is to define intermediate steps in the signalling pathways between receptor stimulation and activation of the cytosolic phospholipase A2. The specific areas of interest are: 1) the role of phosphatidylcholine turnover by phospholipase D in neutrophil and eosinophil responses to allergic challenge; 2) the signalling pathways underlying neutrophil and eosinophil stimulation in response to cytokines (TNFa, GM-CSF) and chemotactic factors (PAF, C5a, 5-hydroxyeicosatetraenoic acid and 5-oxo-15(OH)eicosatetraenoic acid). Our preliminary studies lead to the hypothesis that phospholipase D products are required for the regulation of Raf-1 and the mitogen activated protein kinase pathways. Thus, the stimulation of these systems by the above mentioned cytokines and chemotactic factors will be a focus of this project. To accomplish these overall goals we will pursue the following specific aims: 1) to determine the role of phospholipase D in neutrophil and eosinophil signalling pathways; 2) to define the signalling pathways of neutrophils and eosinophils in response to stimuli. Overall, this project will provide a further understanding of the control of cellular function in response to allergic stimuli and identify targets for pharmacological treatment. It is envisioned that multiple signals contribute to the complete allergic response and no one mediator can be targeted to successfully ameliorate disease outcome. Therefore, multiple strategies of intervention may be required. Our studies of the interactions among cell types and mediators will provide a foundation for these strategies.