HISTONE DEACETYLASES IN EPIGENETIC MODULATION OF MACROPHAGE ACTIVATION AND TRAINING

组蛋白脱乙酰酶在巨噬细胞激活和训练的表观遗传调节中的作用

• 批准号: RGPIN-2018-05514
• 负责人: Kim, SungOuk
• 金额: $ 2.33万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684290
• 关键词: HISTONE; DEACETYLASES; EPIGENETIC; MODULATION; MACROPHAGE

Macrophages are key immune cells which reside in all tissues and orchestrate immune responses. These cells need to be resilient to changing micro-environments to appropriately respond to various challenges. Particularly, adaptation (or training) of macrophages by local microbes and cytokines are crucial for maintaining immunological homeostasis. To date, how macrophages are trained by various microbes and cytokines remains largely unknown. This research will study the mechanisms of macrophage adaptation mediated by live bacteria (L. rhamnosus), bacterial components (anthrax lethal toxin G-CSF) as model systems. The overall goal of our research program is to understand the mechanisms by which macrophages sense, respond and adapt to bacterial microbes and cytokines. Under this goal, we will focus on the following research Aims:*******Aim 1. Examining the role and epigenetic mechanism of the histone deacetylase (HDAC) 8 in macrophage training. Epigenetics is a cellular mechanism that regulates gene expression without altering genomic sequences in response to environmental cues. Among various epigenetic mechanisms, we found that HDAC8 plays a key role in training macrophages by a bacterial toxin, known as anthrax lethal toxin. However, the regulatory mechanisms of HDAC8 and its down-stream pathway involved in macrophage training remain to be addressed. This Aim will study the role and mechanism of HDAC8 in macrophage training by LeTx, L. rhamnosus and G-CSF in the expression of the inflammatory cytokine interleukin-1 as model systems. This Aim will provide new information on the biology of HDAC8 and its mechanism in training macrophages.*******Aim 2. Examining the role of HDACs in macrophage training by intestinal commensals. Training macrophages to respond in an appropriate manner is imperative for immune homeostasis of the intestine, since macrophages must tolerate a heavy load of microbial components, and yet remain vigilant to invading pathogens. In addition to HDAC8, other HDACs are likely involved in training macrophages in the expression of different cytokines. This Aim will examine the role of other HDACs than HDAC8 in regulating expression of different cytokines in macrophages trained by L. rhamnosus and G-CSF as model systems. In addition, this Aim will purify/identify the L. rhamnosus-secreted factor(s) that trains macrophages. Collectively, this Aim will provide new information on the role of HDACs in training macrophages by intestinal microbes and cytokines.*******Overall, our research will provide fundamental information on the epigenetic mechanisms that train macrophages to appropriately respond to microbial components and maintain immunological homeostasis.***

巨噬细胞是存在于所有组织中并协调免疫反应的关键免疫细胞。这些细胞需要适应不断变化的微环境，以适当地应对各种挑战。特别是，巨噬细胞被局部微生物和细胞因子适应（或训练）对于维持免疫稳态至关重要。迄今为止，巨噬细胞是如何被各种微生物和细胞因子训练的，在很大程度上仍然是未知的。本研究将研究活菌（L. rhamnosus）、细菌组分（炭疽致死毒素G-CSF）作为模型系统介导巨噬细胞适应的机制。我们研究项目的总体目标是了解巨噬细胞感知、反应和适应细菌微生物和细胞因子的机制。在此目标下，我们将重点关注以下研究目标：*******Aim 1。研究组蛋白去乙酰化酶（HDAC） 8在巨噬细胞训练中的作用及其表观遗传机制。表观遗传学是一种调节基因表达而不改变基因组序列以响应环境线索的细胞机制。在各种表观遗传机制中，我们发现HDAC8在通过细菌毒素（炭疽致死毒素）训练巨噬细胞中起关键作用。然而，HDAC8及其下游通路参与巨噬细胞训练的调控机制仍有待研究。本实验将以LeTx、鼠李糖和G-CSF为模型系统，研究HDAC8在巨噬细胞训练中对炎性细胞因子白细胞介素-1表达的作用及机制。这一目的将为HDAC8的生物学及其在巨噬细胞训练中的机制提供新的信息。* * * * * * *的目标2。研究hdac在肠道共生体巨噬细胞训练中的作用。训练巨噬细胞以适当的方式作出反应对于肠道的免疫稳态至关重要，因为巨噬细胞必须耐受大量的微生物成分，同时对入侵的病原体保持警惕。除了HDAC8，其他hdac可能参与训练巨噬细胞表达不同的细胞因子。在鼠李糖和G-CSF作为模型系统训练的巨噬细胞中，本研究将研究除HDAC8外的其他hdac在调节不同细胞因子表达中的作用。此外，该Aim将纯化/鉴定培养巨噬细胞的鼠李糖分泌因子。总的来说，这一目的将提供关于hdac在肠道微生物和细胞因子训练巨噬细胞中的作用的新信息。*******总的来说，我们的研究将为培养巨噬细胞对微生物成分做出适当反应并维持免疫稳态的表观遗传机制提供基础信息