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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761035
• 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.

巨噬细胞是关键的免疫细胞，存在于所有组织中并协调免疫反应。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。特别地，通过局部微生物和细胞因子对巨噬细胞的适应（或训练）对于维持免疫稳态至关重要。迄今为止，巨噬细胞如何被各种微生物和细胞因子训练仍然是未知的。本研究旨在探讨活菌介导的巨噬细胞适应机制。rhamnosus）、细菌组分（炭疽致死毒素G-CSF）作为模型系统。我们研究计划的总体目标是了解巨噬细胞感知，响应和适应细菌微生物和细胞因子的机制。在此目标下，我们将集中在以下研究目标：目标1。研究组蛋白去乙酰化酶（HDAC）8在巨噬细胞训练中的作用和表观遗传机制。表观遗传学是一种调节基因表达而不改变基因组序列的细胞机制。在各种表观遗传机制中，我们发现HDAC 8在细菌毒素（称为炭疽致死毒素）训练巨噬细胞中起关键作用。然而，HDAC 8及其下游通路参与巨噬细胞训练的调控机制仍有待解决。本研究旨在探讨HDAC 8在LeTx、L. rhamnosus和G-CSF在表达炎性细胞因子白细胞介素-1方面作为模型系统。本研究为HDAC 8的生物学特性及其在巨噬细胞培养中的作用机制提供了新的信息。检查HDACs在肠道巨噬细胞训练中的作用。训练巨噬细胞以适当的方式做出反应对于肠道的免疫稳态是必要的，因为巨噬细胞必须耐受大量的微生物成分，但仍对入侵的病原体保持警惕。除了HDAC 8之外，其他HDAC可能参与训练巨噬细胞表达不同的细胞因子。本研究旨在探讨除HDAC 8外的其他HDACs在调节L. rhamnosus和G-CSF作为模型系统。此外，本目的还将对L.培养巨噬细胞的鼠李糖分泌因子。总的来说，这个目标将提供新的信息HDACs在训练巨噬细胞的肠道微生物和细胞因子的作用。总的来说，我们的研究将提供基本信息的表观遗传机制，训练巨噬细胞适当地响应微生物成分和维持免疫稳态。