Dietary modulation of macrophage identity: potential impact on nociceptive sensory response

巨噬细胞身份的饮食调节：对伤害性感觉反应的潜在影响

• 批准号: RGPIN-2017-05541
• 负责人: Zhang, Ji
• 金额: $ 2.33万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=669671
• 关键词: Dietary; modulation; macrophage; identity; potential

While eating patterns can help people to achieve/maintain good health, not much is known about how diet affects basic cellular function and physiological ability. As sensing pain is essential for an individual to adapt to its environment and to avoid damage, we want to understand whether (and how) what we eat affects how we feel. We propose a research program with long term objectives to investigate the impact of dietary products on physiological nociceptive response. ***Salt is an essential nutrient required for normal functioning of many types of cells, but it has pro-inflammatory properties. High salt diet (HSD) seen in daily life in westernized society is also a potential candidate disturbing the gut microbiota. In this 5-year research proposal, we will feed healthy C57BL/6 male and female mice with HSD (4% NaCl in chow and 1% NaCl in water) for 3 months to investigate how HSD affects physiological nociceptive response. We will target macrophages (MØs) in the gut and in the nervous system to dissect underlying mechanisms. Our hypothesis is that HSD polarizes gut MØs into pro-inflammatory status, contributing to the development of systemic inflammation, which in turn promotes the activation of MØs/microglia along the pain transmission pathway, leading to enhanced pain sensitivity.***Aim 1: Uncover dietary modulation of MØ identity by analyzing the features of MØs in the gut and MØs/microglia along the pain transmission pathway ***Aim 2: Reveal whether HSD alters nociceptive response to various stimuli by performing a series of behavioral tests ***Aim 3: Dissect underlying mechanisms of HSD-induced alteration in pain sensitivity by:***3.1 Depleting MØs/microglia to understand whether HSD-induced alteration in nociceptive pain behavior requires the participation of MØs.***3.2 Applying HSD to CCD2-/- mice to understand the role of gut MØs in diet-induced alteration of the immune system and nociception. Since gut MØs at adulthood are derived exclusively from CCR2-mediated recruitment and CCR2-/- mice have a considerable deficit in gut MØs.***3.3 Disrupting gut microbiota in mice under HSD with broad spectrum antibiotics to unveil the requirement of gut microbiota in HSD-induced changes in MØ identity and pain sensitivity. ***This research will not only advance significantly our knowledge on how dietary lifestyle alters physiological homeostasis and fundamental functions, but also allow us to pioneer the involvement of microbiota in sensory behavior which is at its very beginning stage.

虽然饮食模式可以帮助人们实现/保持良好的健康，但人们对饮食如何影响基本细胞功能和生理能力知之甚少。由于感知疼痛对于一个人适应环境和避免伤害至关重要，我们想了解我们吃的东西是否（以及如何）影响我们的感受。我们提出了一个具有长期目标的研究计划，以研究膳食产品对生理伤害性反应的影响。* 盐是许多类型细胞正常运作所需的基本营养素，但它具有促炎特性。西方社会日常生活中常见的高盐饮食（HSD）也是扰乱肠道菌群的潜在候选者。在这项为期5年的研究计划中，我们将用HSD（4%NaCl的食物和1%NaCl的水）喂养健康的C57 BL/6雄性和雌性小鼠3个月，以研究HSD如何影响生理伤害性反应。我们将靶向肠道和神经系统中的巨噬细胞（巨噬细胞），以剖析潜在的机制。我们的假设是，HSD将肠道MbS极化为促炎状态，有助于全身炎症的发展，这反过来又促进了MbS/小胶质细胞沿着疼痛传递途径的激活，导致疼痛敏感性增强。目标1：通过分析肠道中MSTs和沿着疼痛传递途径的MSTs/小胶质细胞的特征来揭示MSTs身份的饮食调节 *** 目标2：通过进行一系列行为测试来揭示HSD是否改变对各种刺激的伤害性反应 *** 目标3：通过以下方式来剖析HSD诱导的疼痛敏感性改变的潜在机制：***3.1消耗MSTs/小胶质细胞以了解HSD诱导的伤害性疼痛行为改变是否需要MSTs的参与。*** 3.2将HSD应用于CCD 2-/-小鼠，以了解肠道MIBs在饮食诱导的免疫系统改变和伤害感受中的作用。由于成年期的肠道MMPs仅来源于CCR 2介导的募集，并且CCR 2-/-小鼠在肠道MMPs方面具有相当大的缺陷。3.3用广谱抗生素破坏HSD下小鼠的肠道微生物群，以揭示在HSD诱导的MSH特性和疼痛敏感性变化中肠道微生物群的需求。* 这项研究不仅将大大提高我们对饮食生活方式如何改变生理稳态和基本功能的认识，而且还使我们能够开拓微生物群参与感官行为的最初阶段。