Reprogramming of inflammation, immune cell function, and disease outcomes by the Western Diet

西方饮食对炎症、免疫细胞功能和疾病结果的重新编程

• 批准号: 10390137
• 负责人: Brooke Ann Napier
• 金额: $ 24.69万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390137
• 关键词: Acute; Address; Adult; Automobile Driving; Cell physiology; Cells; Chronic; Chronic Disease; Clinical; Communication; Country; Development; Diet; Dietary Intervention; Disease; Disease Outcome; Endotoxemia; Fatty Acids; Fatty acid glycerol esters; Fiber; Goals; Immune; Immune response; Immunity; Immunologics; Infection; Inflammation; Inflammatory; Innate Immune Response; Intervention; Kinetics; Laboratories; Lead; Lipopolysaccharides; Metabolic; Modeling; Molecular; Natural Immunity; Nutritional; Outcome; Pathway interactions; Play; Population; Process; Regulation; Research; Role; Sepsis; Severities; Shock; Sucrose; System; age related; cell motility; dietary; dietary manipulation; improved; insight; microbial; microbiome; monocyte; mortality; mouse model; neutrophil; novel; programs; systemic inflammatory response; western diet

PROJECT SUMMARY The objective of my laboratory is to characterize how molecular communication between nutritional constituents and innate immune cells lead to diet-dependent altered inflammation and disease outcomes. To accomplish this goal, we have developed a mouse model of dietary manipulation and lipopolysaccharide (LPS)-induced acute inflammation (endotoxemia). This system of acute inflammation is advantageous because we can dissect the relationship between diet and immunity without the confounding factors of an active infection or chronic disease. Using our mouse model, our initial efforts have begun to elucidate the role of Western Diet (WD) in driving chronic systemic inflammation, altered neutrophil and monocyte cell migration and function, and increased severity and mortality in an LPS-driven acute inflammatory shock model (endotoxemia). The WD is a diet high in fat and sucrose and low in fiber, and is the most prevalent diet in Westernized countries (1). The impact of the WD diet on microbiome-associated inflammation has been extensively studied (10-16); however, the molecular mechanisms of WD-associated fatty acids in regulation of inflammation and WD-dependent regulation of the innate immune response to microbial products remain fragmented and poorly characterized. Our goal for the next 5 years is to understand the molecular mechanism by which WD directly regulates immunity and disease kinetics. To accomplish this goal, we will combine multifactorial studies to address undefined paradigms within our field, including: Project 1) Defining the impact of WD-associated fatty acids on monocyte LPS-tolerance and endotoxemia outcome, Project 2) Identifying alternatively regulated pathways in WD-dependent aged neutrophils and elucidate the impact of this cell population on disease outcomes, and Project 3) Elucidating the temporal control and plasticity of immunological reprogramming by WD. This research program focuses on determining the effects of WD on systemic inflammation, cell function, and disease kinetics. A mechanistic understanding of these processes are necessary to develop efficacious dietary strategies to reduce metabolic inflammation and dietary interventions that improve disease outcomes associated with a WD-fed population.

项目摘要 我实验室的目标是描述营养成分之间的分子通讯 和先天免疫细胞导致饮食依赖性改变炎症和疾病结果。为了实现这一 目的，我们已经建立了一个饮食控制和脂多糖（LPS）诱导的急性 炎症（内毒素血症）。这种急性炎症系统是有利的，因为我们可以解剖 饮食和免疫力之间的关系，没有活动性感染或慢性疾病的混杂因素。 使用我们的小鼠模型，我们的初步努力已经开始阐明西方饮食（WD）在驱动慢性炎症中的作用。 全身性炎症、中性粒细胞和单核细胞迁移和功能改变以及严重程度和 LPS驱动的急性炎性休克模型（内毒素血症）中的死亡率。WD是一种高脂肪的饮食， 蔗糖和低纤维，是西方国家最普遍的饮食（1）。WD饮食的影响 对微生物组相关炎症的影响已被广泛研究（10-16）;然而， WD相关脂肪酸调节炎症和WD依赖性调节 对微生物产物的先天免疫反应仍然是零散的，并且特征不明确。我们的目标是 未来5年的目标是了解WD直接调节免疫和疾病的分子机制 动力学。为了实现这一目标，我们将联合收割机多因素研究，以解决未定义的范式内 我们的领域，包括：项目1）定义WD相关脂肪酸对单核细胞LPS耐受性的影响， 内毒素血症结局，项目2）确定WD依赖性老年中性粒细胞的替代调节途径 并阐明该细胞群对疾病结果的影响，以及项目3）阐明 WD对免疫重编程的控制和可塑性。该研究计划的重点是确定 WD对全身炎症、细胞功能和疾病动力学的影响。机械地理解 这些过程对于开发有效的饮食策略以减少代谢性炎症是必要的， 改善与WD喂养人群相关的疾病结局的饮食干预。