SIGNAL TRANSDUCTION IN PMN AND EOSINOPHIL ACTIVATION

描述（申请人摘要）：该计划的长期目标是 确定人类中性粒细胞和嗜酸性粒细胞的信号通路， 对炎症和过敏性攻击的反应。 虽然功能 中性粒细胞对吞噬细胞攻击和趋化因子的反应， 虽然已经被广泛研究，但刺激途径并不详细。 关于中性粒细胞对细胞因子的反应知之甚少。 但 出现了应答吞噬细胞攻击和细胞因子的信号传导途径 与众不同 此外，人们对地球上的信号系统知之甚少。 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 细胞类型特异性的方式相同的炎症和过敏性刺激。 的 特别令人感兴趣的是细胞类型之间的相互作用， 反应过度 具体地说，我们将重点放在刺激， 刺激或引发其他细胞的产物。 我们的目标是定义 在受体刺激之间的信号通路的中间步骤 和胞质磷脂酶A2的活化。 的具体领域 感兴趣的是：1）磷脂酶的磷脂酰胆碱周转的作用 D在中性粒细胞和嗜酸性粒细胞对过敏性激发的反应中; 2） 中性粒细胞和嗜酸性粒细胞刺激的信号通路 对细胞因子（TNF α，GM-CSF）和趋化因子（PAF，C5 α， 5-羟基二十碳四烯酸和5-氧代-15（OH）二十碳四烯酸）。 我们 初步的研究提出了磷脂酶D产物是 调节Raf-1和丝裂原活化蛋白所需的 激酶途径。 因此，通过上述刺激这些系统 上述细胞因子和趋化因子将是本项目的重点。 为了实现这些总体目标，我们将采取以下具体措施： 目的：1）研究磷脂酶D在中性粒细胞和 嗜酸性粒细胞信号通路; 2）确定 嗜中性粒细胞和嗜酸性粒细胞对刺激的反应。 总的来说，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，并确定药理学的目标 治疗 可以设想，多个信号有助于 完全的过敏反应，没有一个介质可以针对 成功改善疾病结果。 因此， 可能需要干预。 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.