A1 REGULATED LEUKOCYTE APOPTOSIS DURING INFLAMMATION

炎症期间 A1 调节白细胞凋亡

• 批准号: 6373872
• 负责人: MICHAEL B PRYSTOWSKY
• 金额: $ 29.25万
• 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/6373872
• 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（改编自研究者的摘要）：细胞凋亡 人们普遍认为炎症白细胞对于调节至关重要 的炎症反应。 对这个想法的直接调查是 由于无法证明特定的调节分子而受到阻碍 这些细胞可能允许对细胞凋亡进行实验操作 回复。 我们已经分离并描述了这样一个候选分子，Bcl-2 相关的抗凋亡蛋白命名为A1。 A1 被快速诱导 巨噬细胞受到促炎介质的影响，并且被强烈上调 在小鼠急性致病炎症期间。 该项目的目标 旨在阐明A1在调节细胞死亡中的功能作用 炎症反应的进展和消退过程。 这 应用提出了急性反应中细胞凋亡调节的模型 病原体分为两个阶段。 在第一阶段，先天免疫 反应会产生至关重要的效应分子，例如一氧化氮 用于宿主防御，但也促进巨噬细胞凋亡。 在这个阶段， A1 表达保护巨噬细胞并允许炎症反应 继续。 在第二阶段，病原体已被大部分清除，并且 炎症巨噬细胞现在被第二波促凋亡细胞清除 刺激。 第二波可能源自激活的 T 细胞， 能够超越A1的保护作用。 具体目标将测试 并完善这一想法将集中于以下三个假设：（1） 宿主防御的调解者包括“A1 敏感”和“A1 抗性” 凋亡刺激。 (2)在弓形虫感染的急性反应过程中， 炎症环境中发生了 A1 介导的保护的转变 巨噬细胞对 A1 耐药的巨噬细胞凋亡。 (3) 保护 炎症期间的巨噬细胞由 A1 介导，对宿主至关重要 防御。

项目成果

Transient expression of the Bcl-2 family member, A1-a, results in nuclear localization and resistance to staurosporine-induced apoptosis.

Bcl-2 家族成员 A1-a 的瞬时表达导致核定位和对十字孢菌素诱导的细胞凋亡的抵抗。

• DOI: 10.1038/sj.cdd.4400879
• 发表时间: 2001
• 期刊: Cell death and differentiation.
• 作者: Somogyi,RD;Wu,Y;Orlofsky,A;Prystowsky,MB
• 通讯作者: Prystowsky,MB