Regulatory T Cells in Alzheimer's Disease

阿尔茨海默病中的调节性 T 细胞

• 批准号: 10685434
• 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/10685434
• 关键词: Affect; Age Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Applications Grants; Attenuated; Brain; Cell physiology; Cells; Characteristics; Comparative Study; Diphtheria Toxin; Disease; Disease Progression; FOXP3 gene; Functional disorder; Future; Goals; Human; IL2 gene; IL2RA gene; Immune response; Inflammation; Inflammatory; Innate Immune Response; 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 cell therapy; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; T-cell diversity; Testing; Time; Tissue Model; Tissues; Transgenic Mice; Work; adaptive immune response; clinically relevant; glial activation; 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.

项目总结 最近的研究表明，获得性免疫反应在阿尔茨海默氏症中起着重要作用 通过促进大脑中的促炎状态来促进疾病(AD)的进展。这一炎症过程涉及到 T细胞和小胶质细胞活化。这种炎症过程通常被T细胞亚群抑制 称为调节性T细胞(Tregs)。值得注意的是，在人类和小鼠中，Treg功能障碍与AD有关 AD的模型。除了AD病例中Tregs的减少外，研究还表明，全身衰竭 在转基因动物中，Tregs的增加加剧了早期AD的病理，而Tregs的增加缓解了早期的AD病理 阿尔茨海默病小鼠模型。然而，这些先前的研究都有重要的警告。首先，所有涉及 Treg depletion专注于在AD病理的早期阶段对年轻小鼠的研究，这可能不是临床上的 相关时间点。第二，利用FOXP3-DTR小鼠和白喉毒素选择性消耗Treg的研究 耗尽所有的Tregs，并引发全身炎症。这使得很难评估是否会更糟 在AD中观察到的“Treg耗竭”的结果特定于Treg在大脑中的影响或由于大量的 全身炎症。此外，在AD进展过程中积累的Tregs的类型及其功能 在疾病进展中的作用，特别是在大脑中的作用，也是未知的。因此，我们知识中的主要差距是 (I)在稳态和阿尔茨海默病期间，在大脑中发现了哪些类型的Treg；及(Ii) Tregs或Tregs的不同子集在改善AD方面扮演什么角色。我们的初步研究表明 组织中的Treg非常多样化，不同的Treg亚群占据了不同的炎症组织 运动学。最值得注意的是，我们发现了一种新的Tregs种群，称为ISG-Tregs，它聚集在组织中 由干扰素引起的炎症。先前对AD的研究表明，I型干扰素是AD的一个特征， 它会加重AD模型的神经损害，并在引发神经炎症中发挥重要作用 和促进AD进展。因此，ISG-Tregs可能在AD的进展中起关键作用。这样做的目的是 建议是确定大脑中存在的Tregs的子集，并确定这些子集在哪里 位于大脑内，在AD进展过程中，并建立小鼠模型来直接测试功能 公元中的Tregs和Treg子集。我们将使用scRNA-Seq和空间蛋白质组/转录组学方法来 描述AD进展过程中的Tregs特征。使用我们开发的一种新型Treg报告/Deleter小鼠品系 我们还将开发新的小鼠模型，使我们能够研究大脑树的功能，或选择大脑 关于AD进展的Treg子集。我们还将提供有关AFP的病理作用的重要信息 在体内AD不同阶段的Treg。这些研究将使我们能够表征存在于 AD，在疾病发展过程中建立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重阿尔茨海默病方面的功能作用。这样的信息 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结果至关重要。