A1 REGULATED LEUKOCYTE APOPTOSIS DURING INFLAMMATION

炎症期间 A1 调节白细胞凋亡

• 批准号: 2887788
• 负责人: MICHAEL B PRYSTOWSKY
• 金额: $ 27.57万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887788
• 关键词: BCL2 gene /protein; Toxoplasma gondii; apoptosis; cell growth regulation; cellular immunity; fluorimetry; gene targeting; genetically modified animals; host organism interaction; inflammation; intracellular parasitism; laboratory mouse; leukocyte activation /transformation; leukocytes; macrophage; nitric oxide; pathologic process; protein structure function; single cell analysis; toxoplasmosis; western blottings

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.

描述（改编自研究者摘要）： 炎症性白细胞被广泛认为是至关重要的调节 炎症反应。 对这一想法的直接调查 由于无法证明特定于 这些细胞可能允许实验操作的凋亡 反应 我们已经分离并描述了这样一个候选分子，Bcl-2 相关的抗凋亡蛋白A1。 A1是快速诱导的 巨噬细胞的促炎介质，并强烈上调 在小鼠的急性致病性炎症中。 本项目的目标 目的是阐明A1在细胞死亡调控中的功能作用 在炎症反应的进展和解决过程中。 的 本申请提出了一种急性反应中细胞凋亡调节的模型 转化为病原体分为两个阶段。 在第一阶段，先天免疫 反应产生效应分子，如一氧化氮，这是至关重要的 用于宿主防御，但也对巨噬细胞促凋亡。 在这一阶段， A1表达保护巨噬细胞并允许炎症反应 继续 在第二阶段，病原体已基本清除， 炎症巨噬细胞现在被第二波促凋亡细胞因子清除， 刺激。 第二波可能来自活化的T细胞， 能够克服A1的保护作用。 具体目标将测试 并对这一思路进行细化，将重点放在以下三个假设上：（1） 宿主防御的调节因子包括"A1敏感"和"A1抗性" 凋亡刺激。 (2)在T.弓形虫感染 在炎症环境中发生了从A1介导的保护， 巨噬细胞对A1抗性巨噬细胞凋亡的影响。 (3)保护 A1介导巨噬细胞在炎症过程中的表达， 防御