Regulatory T Cells in Alzheimer's Disease

阿尔茨海默病中的调节性 T 细胞

• 批准号: 10515396
• 负责人: Michael Archibald Farrar
• 金额: $ 76.88万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515396
• 关键词: Adoptive Transfer; Affect; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Applications Grants; Attenuated; Birds; Brain; Case Study; Cells; Characteristics; Comparative Study; Diphtheria Toxin; Disease; Disease Progression; FOXP3 gene; Functional disorder; Future; Goals; Human; IL2 gene; IL2RA gene; Immune response; Inflammation; Inflammatory; Interferons; Investigation; Kinetics; Knowledge; Label; Location; Microglia; Modeling; Mouse Strains; Mus; NRP1 gene; Nervous System Trauma; Outcome; Pathogenesis; Pathologic; Play; Population; Process; Proteomics; Protocols documentation; Regulatory T-Lymphocyte; Reporter; Role; Symptoms; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissue Model; Tissues; Transgenic Mice; Work; adaptive immune response; base; clinically relevant; improved outcome; in vivo; mouse model; neuroinflammation; novel; prevent; repaired; single-cell RNA sequencing; systemic inflammatory response; transcriptomics

PROJECT SUMMARY Recent studies have demonstrated that the adaptive immune response plays an important role Alzheimer’s disease (AD) progression by promoting a pro-inflammatory state in the brain. This inflammatory process involves T cell and microglial cell activation. Such inflammatory processes are typically suppressed by a subset of T cells called regulatory T cells (Tregs). Significantly, Treg dysfunction is associated with AD in humans and in mouse models of AD. In addition to decreased Tregs in AD cases, studies have demonstrated that systemic depletion of Tregs exacerbates early AD pathology, while an increase in Tregs attenuates early AD pathology in transgenic mouse models of AD. However, these previous studies come with important caveats. First, all studies involving Treg depletion focused on studies in young mice at early stages of AD pathology, which may not be a clinically relevant time-point. Second, studies using FOXP3-DTR mice and diphtheria toxin to selectively deplete Tregs deplete Tregs everywhere and induce body-wide inflammation. This makes it difficult to assess whether worse outcomes observed in AD upon “Treg depletion” are specific to an effect of Tregs in the brain or due to massive systemic inflammation. Moreover, the types of Tregs that accumulate during AD progression, and their functional role in disease progression, particularly in brain, are also unknown. Thus, major gaps in our knowledge are (i) what types of Tregs are found in the brain during steady-state and in Alzheimer’s disease and, (ii) what role Tregs or distinct subsets of Tregs play in ameliorating AD. Our preliminary studies demonstrate that Tregs in tissues are quite diverse and that distinct Treg subsets occupy inflamed tissues with different kinetics. Most notably, we identified a novel population of Tregs, called ISG-Tregs, that accumulate in tissues with IFN-driven inflammation. Previous studies of AD demonstrate that type I IFN is a characteristic of AD, that it exacerbates neurological damage in AD models, and plays an important role in initiating neuroinflammation and promoting AD progression. Thus, ISG-Tregs may play a critical role in AD progression. The goal of this proposal is to identify the subsets of Tregs present in the brain, and identify where those subsets are located within the brain, during AD progression, and establish murine models to directly test the function of Tregs and Treg subsets in AD. We will use scRNA-Seq and spatial proteomic/transcriptomic approaches to characterize Tregs during AD progression. Using a novel Treg reporter/deleter mouse strain that we developed we will also develop new mouse models that will allow us to study the function of brain Tregs, or select brain Treg subsets, on AD progression. We will also provide important information regarding the pathological role of Treg at different stages of AD in vivo. These studies will allow us to characterize the types of Tregs present in AD, establish their localization in the brain during disease progression, and develop models that will allow us to establish their functional role in ameliorating or exacerbating Alzheimer’s disease in the future. Such information will prove critical for better implementation of Treg-based therapies to improve outcomes in Alzheimer’s disease.

项目概要 最近的研究表明，适应性免疫反应在阿尔茨海默病中发挥着重要作用 通过促进大脑中的促炎症状态来促进疾病（AD）的进展。这种炎症过程涉及到。 T 细胞和小胶质细胞的激活通常被 T 细胞亚群抑制。 值得注意的是，Treg 功能障碍与人类和小鼠的 AD 相关。 AD 模型除了 AD 病例中 Tregs 减少外，研究还表明全身性耗竭。 Tregs 的增加使早期 AD 病理恶化，而转基因中 Tregs 的增加则减弱早期 AD 病理 然而，这些先前的研究都有重要的警告：首先，所有研究都涉及。 Treg 耗竭的研究重点是在 AD 病理学早期阶段的年轻小鼠中，这可能不具有临床意义。 其次，使用 FOXP3-DTR 小鼠和白喉毒素选择性消耗 Tregs 的研究。 耗尽各处的 Tregs 并诱发全身炎症，这使得很难评估是否更糟。 在 AD 中观察到的“Treg 耗竭”结果是特定于大脑中 Tregs 的作用或由于大量 此外，在系统性 AD 进展过程中积累的 Tregs 类型及其功能。 在疾病进展中的作用，特别是在大脑中，我们的知识还存在重大差距。 (i) 在稳态期间和阿尔茨海默氏病的大脑中发现了哪些类型的 Tregs，以及 (ii) 我们的初步研究证明了 Tregs 或 Tregs 的不同子集在改善 AD 方面发挥什么作用。 组织中的 Treg 非常多样化，并且不同的 Treg 亚群以不同的方式占据发炎组织 最值得注意的是，我们发现了一种新的 Tregs 群体，称为 ISG-Tregs，它们在组织中积累。 先前对 AD 的研究表明，I 型 IFN 是 AD 的一个特征，即 它会加剧 AD 模型中的神经损伤，并在引发神经炎症中发挥重要作用 因此，ISG-Tregs 可能在 AD 进展中发挥关键作用。 提议是识别大脑中存在的 Tregs 子集，并确定这些子集的位置 AD进展期间位于大脑内，并建立小鼠模型以直接测试功能 我们将使用 scRNA-Seq 和空间蛋白质组学/转录组学方法来分析 AD 中的 Tregs 和 Treg 子集。 使用我们开发的新型 Treg 报告/删除小鼠品系表征 AD 进展过程中的 Tregs。 我们还将开发新的小鼠模型，使我们能够研究大脑 Tregs 的功能，或者选择大脑 Treg 亚群对 AD 进展的影响 我们还将提供有关 AD 病理作用的重要信息。 体内 AD 不同阶段的 Tregs 将使我们能够表征体内存在的 Tregs 类型。 AD，在疾病进展过程中确定它们在大脑中的定位，并开发模型使我们能够 确定它们在未来改善或加剧阿尔茨海默病中的功能作用。 事实证明，这对于更好地实施基于 Treg 的疗法以改善阿尔茨海默病的治疗结果至关重要。