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 尿路感染（UTI）主要是由尿路病大肠杆菌（UPEC）引起的 老年妇女复发，这是一个重大的健康问题。虽然有很多因素有助于这 易感性提高，与年龄相关的巨噬细胞功能变化也可能起作用。巨噬细胞是 由先天免疫细胞招募为急救人员，以帮助控制感染：识别和 内部化病原体降解；提出抗原以募集适应性免疫反应；和 编排组织炎症。先前的研究表明巨噬细胞成为功能失调 随着年龄的一部分，部分归因于脂质稳态的扰动。例如，脂肪酸饱和酶 stearoyl-COA去饱和酶2（SCD2）随着年龄的增长而下调。但是，SCD2在维护中的作用 巨噬细胞在感染中的功能尚不清楚。初步数据表明SCD2缺陷率 巨噬细胞无法消除内部化的UPEC，这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，SCD2的不足会改变脂质 细胞膜的组成，从而破坏膜依赖性过程，例如 自噬体融合与溶酶体，用于降解或细胞呼吸 膜。因此，AIM 1将在体外研究SCD2缺陷巨噬细胞，以进一步阐明这些缺陷 细胞和分子过程增加了对UPEC感染的敏感性。 AIM 2将确定是否 巨噬细胞SCD2在UTI小鼠模型中对UPEC感染的宿主反应中起重要作用。 这项研究的完成将对SCD2介导的脂质的机制有更深入的了解 代谢保持基本巨噬细胞免疫功能，这是一个重要的知识差距 该领域以及对巨噬细胞和衰老中脂质代谢的现有理解的扩展。 此外，这项工作可能揭示了老年人经常性UTI的临床管理的新策略， 对于哪些治疗仍然不足。以及以学生为中心的培训计划和严格的 协作研究环境，拟议的研究还将使PI扩展现有并获取 新的技术，科学和专业技能将是成为独立研究者的关键。到 进一步增强培训，包括整合临床活动并准备PI过渡的策略 到他们职业生涯的下一个阶段。