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

摘要 尿路感染主要由尿路致病性大肠杆菌引起。大肠杆菌（UPEC）有很高的 复发在老年妇女，一个主要的健康问题。虽然有很多因素导致了这一点， 增加的易感性、年龄相关的巨噬细胞功能变化也可能起作用。巨噬细胞是 先天免疫细胞作为第一反应者被招募，通过以下方式帮助控制感染： 呈递抗原以募集适应性免疫应答;以及 引起组织炎症以前的研究已经证明，巨噬细胞变得功能失调， 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（SCD 2）随着年龄的增长而下调。然而，SCD 2在维持 巨噬细胞在感染中的功能尚不清楚。初步数据表明， 巨噬细胞清除内化的UPEC的能力较低，可能是由于自噬体的缺陷。 降解和线粒体功能。提出了SCD 2缺陷改变脂质的模型 细胞膜的组成，从而破坏膜依赖性过程，如 自噬体与溶酶体融合，用于降解或穿过内部线粒体的细胞呼吸 膜的因此，目的1将在体外研究SCD 2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感染的易感性的细胞和分子过程。目标2将决定是否 巨噬细胞SCD 2在UTI小鼠模型中对UPEC感染的宿主应答中起重要作用。 这项研究的完成将使我们更深入地了解SCD 2介导的脂质代谢的机制。 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，以及扩大对巨噬细胞和衰老的脂质代谢的现有认识。 此外，这项工作可能揭示老年人复发性UTI临床管理的新策略， 治疗仍然不足。以学生为中心的培训计划和严格的，但 合作研究环境，拟议的研究还将使PI扩展现有的，并获得 新的技术，科学和专业技能，这将是成为一名独立调查员的关键。到 进一步加强培训，包括整合临床活动和准备PI过渡的策略 他们职业生涯的下一个阶段。

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.