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.

项目摘要 近年来的研究表明，适应性免疫反应在阿尔茨海默病的发病中起着重要作用 通过促进脑中的促炎状态来控制疾病（AD）进展。这种炎症过程涉及 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 调节性T细胞（Regulatory T cells，Tcells）值得注意的是，Treg功能障碍与人类和小鼠中的AD相关 AD模型除了AD病例中TdR降低外，研究表明全身性消耗 在转基因小鼠中，TdR的增加加重了早期AD病理，而TdR的增加减弱了早期AD病理。 AD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耗竭集中在AD病理学早期阶段的年轻小鼠中的研究，这可能不是临床上的一个问题。 相关时间点。第二，使用FOXP 3-DTR小鼠和白喉毒素选择性地消耗TcB的研究， 耗尽全身的T细胞并引起全身炎症。这使得很难评估是否更糟 在AD中观察到的“Treg耗竭”后的结果特异于脑中TdR的作用，或由于大量的TdR的作用。 全身炎症。此外，在AD进展过程中积累的TdR类型及其功能性 在疾病进展中的作用，特别是在脑中的作用也是未知的。因此，我们知识的主要差距是 (i)在稳态和阿尔茨海默病的大脑中发现了哪些类型的TbR，以及（ii） TdR或TdR的不同子集在改善AD中起什么作用。我们的初步研究表明 组织中的Treg是非常多样的，不同的Treg亚群占据具有不同 动力学。最值得注意的是，我们发现了一种新的Tclase群体，称为ISG-Tclase， IFN驱动的炎症既往对AD的研究表明，I型干扰素是AD的一个特征，即 在AD模型中，它加重神经损伤，并在引发神经炎症中起重要作用 并促进AD进展。因此，ISG-TdR可能在AD进展中起关键作用。这个目标 一个建议是识别大脑中存在的TdR亚群，并识别这些亚群的位置。 位于大脑内，在AD进展期间，并建立小鼠模型以直接测试功能 AD患者的T细胞亚群和Treg亚群。我们将使用scRNA-Seq和空间蛋白质组学/转录组学方法， 在AD进展期间表征TdR。使用我们开发的新型Treg报告/删除小鼠品系， 我们还将开发新的小鼠模型，使我们能够研究大脑Tactus的功能，或选择大脑 Treg亚群，AD进展。我们还将提供关于以下病理作用的重要信息： 在体内AD的不同阶段的Treg。这些研究将使我们能够表征存在于 AD，在疾病进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中的功能作用。此类信息 将证明对更好地实施基于Treg的治疗以改善阿尔茨海默病的结果至关重要。