A1 REGULATED LEUKOCYTE APOPTOSIS DURING INFLAMMATION

描述(改编自调查者摘要)：细胞凋亡 人们普遍认为炎性白细胞在这一调节中起关键作用。 炎症反应。对这一想法的直接调查已经被 受阻于无法证明特定于 这些细胞可能允许对细胞凋亡的实验操作 回应。我们已经分离并描述了这样一个候选分子，即Bcl2 相关抗凋亡蛋白命名为A1。A1在体内被迅速诱导 巨噬细胞通过促炎介质，并被强烈上调 在小鼠急性致病性炎症期间。这个项目的目标是 是阐明A1在调节细胞死亡中的功能作用 炎症反应进展和消退过程中的过程。这个 应用程序提出急性反应中的细胞凋亡调控模型 对病原体的致病分为两个阶段。在第一阶段，先天免疫 反应产生的效应分子，如一氧化氮，是至关重要的 用于宿主防御，但对巨噬细胞也是促凋亡的。在这个阶段， A1的表达保护巨噬细胞并允许炎症反应 才能继续。在第二阶段，病原体已基本清除， 炎性巨噬细胞现在被第二波促凋亡浪潮清除 刺激物。这第二波可能来自激活的T细胞，是 能够超越A1的保护作用。具体的目标将是考验 而细化这一思路将重点放在以下三个假设上：(1) 寄主防御的介体包括‘A1敏感’和‘A1抗性’。 细胞凋亡性刺激。(2)在对弓形虫感染的急性反应中，a 炎症环境发生变化，从A1介导的保护 巨噬细胞向抗A1的巨噬细胞凋亡。(3)保障 炎症过程中的巨噬细胞由A1介导，对宿主至关重要 防守。

DESCRIPTION (Adapted from the Investigator's abstract): Apoptosis of inflammatory leukocytes is widely thought to be crucial for the regulation of inflammatory responses. The direct investigation of this idea has been hampered by the inability to demonstrate regulatory molecules specific to these cells that might permit experimental manipulation of the apoptotic response. We have isolated and described such a candidate molecule, a Bcl-2 related anti-apoptotic protein named A1. A1 is rapidly induced in macrophages by pro-inflammatory mediators, and is strongly up-regulated during acute pathogenic inflammation in mice. The objective of this project is to clarify the functional roles of A1 in the regulation of cell death processes during the progress and resolution of inflammatory responses. The application proposes a model for apoptotic regulation in the acute response to a pathogen is divided into two stages. In stage one, the innate immune response generates effector molecules such as nitric oxide that are vital for host defense but are also pro-apoptotic for macrophages. At this stage, A1 expression protects the macrophage and permits the inflammatory response to continue. In stage two, pathogen has been largely cleared, and inflammatory macrophages are now removed by a second wave of pro-apoptotic stimuli. This second wave, which may be derived from activated T-cells, is able to override the protective effects of A1. The Specific Aims will test and refine this idea will focus on the following three hypotheses: (1) Mediators of host defense include both 'A1-sensitive' and 'A1-resistant' apoptotic stimuli. (2) During the acute response to T. gondii infection, a shift occurs in the inflammatory environment from A1-mediated protection of macrophages to A1-resistant macrophage apoptosis. (3) Protection of macrophages during inflammation is mediated by A1 and is vital for host defense.