NON-CONTACT BASED INTERCELLULAR COMMUNICATION ON NEUTROP

描述 （摘自申请人摘要）目的：本研究的目标 建议研究嗜中性粒细胞-中性粒细胞通讯的机制， 包括触摸，或扩散性中性粒细胞串扰， 中性粒细胞并产生组织炎症。 假设：1. 活跃的人类多形核中性粒细胞（PMN）分泌 作用于远处PMN的信使，使其激活独立于 其他刺激。 2. 多个PMN的连续激活取决于 转导、扩增、繁殖和延长 激活信号 3. 这种细胞间的数学模型 沟通过程可能会提高我们对疾病的理解， 全身性急性或慢性炎症， 暂时性伤害 研究计划：本项目将采用多学科方法进行探索 嗜中性粒细胞-嗜中性粒细胞相互作用的性质导致细胞 activation. 第一个具体目标是确定和描述 扩散性PMN串扰的媒介物。 使用源自补丁的技术 钳位研究，它们将激活单个PMN，而非激活 表面。 使用多种光学显微镜技术，他们将描述和 测量细胞间活化的过程。 通过使用已知的 中性粒细胞分泌的分子，研究人员将确定 实际的细胞间信使和测量的影响， 分子，如蛋白酶和活性氧。 第二 一个具体的目的是描述多个PMN远端的连续激活， 一个最初被激活的细胞。 使用细胞内标记和阻断 主要的细胞内介质的激活，他们将量化和 描述信号的转导途径，并检查 PMN放大、延长和传播激活信号的能力。 的 第三个具体目标是对源自单个 激活PMN。 使用数值分析技术，我们将模拟 在分子水平上的细胞间激活剂的扩散，并比较 通过实验观察。 通过整合转导信息 和微观解剖学的知识，研究人员将扩大 模型来检查在细胞处传播PMN激活波的效果， 组织和器官水平。 重要性：成功完成本提案将改善 了解促进炎症过程的基本机制， 是急性和慢性炎症性疾病的基础。

DESCRIPTION (Adapted from the applicant's abstract) Objective: The goal of this proposal is to study mechanisms of neutrophil-neutrophil communication not involving touch, or diffusive neutrophil crosstalk, that activate neutrophils and produce tissue inflammation. Hypotheses: 1. Active human polymorphonuclear neutrophils (PMN) secrete messengers that act on distant PMN causing their activation independent of other stimuli. 2. The serial activation of multiple PMN depends on transduction, amplification, propagation and prolongation of the original activating signal. 3. Mathematical modeling of this intercellular communication process may improve our understanding of diseases involving generalized acute or chronic inflammation originating from localized and temporary injury. Research Plan: This project will use multi-disciplinary methods to explore the nature of neutrophil-neutrophil interactions leading to cellular activation. The first specific aim is to identify and characterize the agent(s) of diffusive PMN crosstalk. Using techniques derived from patch clamping studies they will activate single PMN resting on non-activating surfaces. Using multiple light microscopy techniques they will describe and measure the process of intercellular activation. By using blockers of known secreted molecules of neutrophils, the investigators will identify the actual intercellular messenger and measure the effects of PMN secreted molecules, such as proteinases and reactive oxygen species. The second specific aim is to describe the serial activation of multiple PMN distant from an initially activated cell. Using intracellular markers and blockade of major intracellular mediators of activation, they will quantify and describe the transduction pathway of a signal and examine the transponding ability of PMN to amplify, prolong and propagate activation signals. The third specific aim is to model activation waves originating from singly activated PMN. Using numerical analytic techniques we will model the diffusion of intercellular activators at the molecular level and compare with experimental observations. By incorporating transduction information and knowledge of microscopic anatomy, the investigators will extend the model to examine the effect of propagating PMN activation waves at cell, tissue and organ levels. Significance: Successful completion of this proposal promises an improved understanding of basic mechanisms that promote inflammatory processes that underlie acute and chronic inflammatory diseases.