Role of stearoyl-CoA desaturase 2 in macrophage-mediated antimicrobial immunity

硬脂酰辅酶A去饱和酶2在巨噬细胞介导的抗菌免疫中的作用

• 批准号: 10312213
• 负责人: Joseph B Lin
• 金额: $ 3.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312213
• 关键词: Affect; Age; Aging; Antigens; Autophagocytosis; Autophagosome; Bacteria; Bacterial Infections; Biological Assay; Bladder; Bone Marrow; Cardiolipins; Cell Respiration; Cell physiology; Cells; Cellular Membrane; Chimera organism; Clinical; Clinical Management; Data; Defect; Disease; Elderly; Elderly woman; Environment; Enzymes; Escherichia coli Infections; Exhibits; Fatty Acid Desaturases; Fatty Acids; Functional disorder; Genes; Genus Hippocampus; Harvest; Health; High Prevalence; Homeostasis; Immune; Immune response; Immunity; Impairment; In Vitro; Infection; Infection Control; Infectious Agent; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Inner mitochondrial membrane; Interleukins; Knowledge; Link; Lipids; Lysosomes; Measurement; Mediating; Membrane; Membrane Fusion; Membrane Lipids; Mitochondria; Modeling; Molecular; Mus; Pathologic; Pathway interactions; Physiological; Play; Predisposition; Process; Production; Public Health; Reactive Oxygen Species; Recurrence; Research; Research Personnel; Resolution; Risk; Role; Stearoyl-CoA Desaturase; Students; Testing; Tissues; Training; Unsaturated Fatty Acids; Urinary tract infection; Uropathogenic E. coli; Woman; Work; adaptive immune response; age related; antimicrobial; career; clinically significant; cytokine; experience; experimental study; first responder; gene induction; immune function; in vivo; lipid metabolism; macrophage; mitochondrial metabolism; monocyte; mouse model; novel; novel strategies; pathogen; programs; recruit; research study; response; skills; systemic inflammatory response; targeted treatment; wasting

ABSTRACT Urinary tract infections (UTIs) predominantly caused by uropathogenic E. coli (UPEC) have a high rate of recurrence in elderly women, a major health problem. Though there are many factors that contribute to this increased susceptibility, age-related changes in macrophage function may also play a role. Macrophages are innate immune cells that are recruited as first responders to help control infection by: recognizing and internalizing pathogens for degradation; presenting antigens to recruit the adaptive immune response; and orchestrating tissue inflammation. Previous studies have demonstrated that macrophages become dysfunctional with age due in part to perturbations in lipid homeostasis. For instance, the fatty acid-desaturating enzyme stearoyl-CoA desaturase 2 (SCD2) becomes downregulated with age. However, the role of SCD2 in maintaining macrophage functions in infection is not clearly understood. Preliminary data indicate that SCD2-deficient macrophages are less able to eliminate internalized UPEC, perhaps due to deficits in autophagosome degradation and mitochondrial function. A model is proposed by which deficiency of SCD2 alters the lipid composition of cellular membranes thereby disrupting membrane-dependent processes, such as autophagosome fusion with lysosomes for degradation or cellular respiration across the inner mitochondrial membrane. Therefore, aim 1 will study SCD2-deficient macrophages in vitro to further elucidate these defective cellular and molecular processes that increase susceptibility to UPEC infection. Aim 2 will determine whether macrophage SCD2 plays an important role in the host response to UPEC infection in a mouse model of UTI. Completion of this study will provide a deeper understanding of the mechanism by which SCD2-mediated lipid metabolism maintains fundamental macrophage immune functions, an important knowledge gap that remains in the field, as well as expand on the existing understanding of lipid metabolism in macrophages and aging. Additionally, this work may reveal novel strategies for the clinical management of recurrent UTIs in the elderly, for which treatments remain inadequate. Together with a student-focused training plan and rigorous but collaborative research environment, the proposed study will also enable the PI to extend existing and acquire new technical, scientific, and professional skills that will be key to becoming an independent investigator. To further enhance training, a strategy is included to integrate clinical activities and prepare the PI for transitioning to the next stage of their career.

抽象的 主要由尿路致病性大肠杆菌 (UPEC) 引起的尿路感染 (UTI) 发病率很高 老年妇女的复发是一个主要的健康问题。虽然造成这种情况的因素有很多 易感性增加、年龄相关的巨噬细胞功能变化也可能发挥作用。巨噬细胞是 先天免疫细胞被招募为第一反应者，通过以下方式帮助控制感染：识别和 内化病原体进行降解；呈递抗原以招募适应性免疫反应；和 协调组织炎症。先前的研究表明巨噬细胞功能失调 随着年龄的增长，部分原因是脂质稳态的扰动。例如，脂肪酸去饱和酶 硬脂酰辅酶 A 去饱和酶 2 (SCD2) 随着年龄的增长而下调。然而，SCD2 在维持 巨噬细胞在感染中的功能尚不清楚。初步数据表明 SCD2 缺陷 巨噬细胞消除内化 UPEC 的能力较差，可能是由于自噬体的缺陷 降解和线粒体功能。提出了一个模型，通过该模型，SCD2 的缺乏会改变脂质 细胞膜的组成，从而破坏膜依赖性过程，例如 自噬体与溶酶体融合，用于降解或穿过线粒体内部的细胞呼吸 膜。因此，目标1将在体外研究SCD2缺陷型巨噬细胞，以进一步阐明这些缺陷型巨噬细胞。 增加对 UPEC 感染易感性的细胞和分子过程。目标 2 将确定是否 在 UTI 小鼠模型中，巨噬细胞 SCD2 在宿主对 UPEC 感染的反应中发挥着重要作用。 这项研究的完成将使人们更深入地了解 SCD2 介导的脂质 新陈代谢维持基本的巨噬细胞免疫功能，这是一个重要的知识空白 该领域，并扩展对巨噬细胞脂质代谢和衰老的现有理解。 此外，这项工作可能揭示老年人复发性尿路感染临床管理的新策略， 对此治疗仍然不足。加上以学生为中心的培训计划和严格但 协作研究环境，拟议的研究还将使 PI 能够扩展现有的并获取 新技术、科学和专业技能将是成为独立调查员的关键。到 进一步加强培训，其中包括整合临床活动并为 PI 过渡做好准备的策略 到他们职业生涯的下一个阶段。