NON-CONTACT BASED INTERCELLULAR COMMUNICATION ON NEUTROP

描述 (改编自申请者的摘要)目的：本报告的目的 建议研究中性粒细胞-中性粒细胞通讯机制 涉及触摸，或扩散的中性粒细胞串扰，激活 中性粒细胞和产生组织炎症。 假设：1.活动性人中性粒细胞(PMN)分泌 作用于远程PMN的信使独立于 其他刺激物。2.多个PMN的串联激活依赖于 原文的转导、扩增、传播和延伸 激活信号。3.细胞间相互作用的数学模型 沟通过程可能会提高我们对疾病的理解 广泛性急性或慢性炎症起源于局部和 暂时的伤害。 研究计划：该项目将使用多学科方法来探索 中性粒细胞-中性粒细胞相互作用的本质导致细胞 激活。第一个具体目标是识别和描述 扩散型PMN串扰诱导剂S。使用从补丁派生的技术 钳制研究他们将在不激活的情况下激活单个PMN 表面。使用多种光学显微镜技术，他们将描述和 测量细胞间激活的过程。通过使用已知的阻滞剂 中性粒细胞的分泌分子，调查人员将确定 实际细胞间信使和测量中性粒细胞分泌的影响 分子，如蛋白水解酶和活性氧物种。第二 具体目的是描述多个PMN远程串联激活 来自一个最初激活的细胞。使用细胞内标记和阻断 主要的细胞内激活介质，他们将量化和 描述信号的转导路径并检查应答器 PMN能够放大、延长和传播激活信号。这个 第三个特定的目标是模拟单个来源的激活波 已激活PMN。使用数值分析技术，我们将对 细胞间激活剂在分子水平上的扩散及比较 并进行了实验观察。通过整合转导信息 和显微解剖学的知识，研究人员将扩展 研究PMN激活波在细胞中传播的影响的模型， 组织和器官水平。 意义：这项提案的成功完成保证了 对促进炎症过程的基本机制的理解 急性和慢性炎症性疾病是其基础。

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.