Proj 3 - Dysregulation of hematopoiesis and peripheral immune function and autophagy in aging and age-related diseases

适应性免疫和先天性免疫的功能变化有助于衰老过程中的免疫衰老。的 免疫系统也与炎症、自身免疫和减少蛋白质聚集有关 阿尔茨海默病（AD）患者大脑中的清除率。衰老的免疫细胞拥有广泛的 自噬途径受损，包括巨自噬（MA）和分子伴侣介导的自噬 (CMA)，这会触发关键免疫细胞亚群的功能改变，如T细胞和单核细胞衍生的 巨噬细胞衰老相关的自噬活性降低的机制和 全面描述其功能性后果仍然难以捉摸，但可能是关键 用于开发创新的新疗法，以对抗与衰老相关的神经退行性过程 和病理学，包括AD和AD相关痴呆。 在本PP的前几期，我们已经确定了免疫系统中自噬的新的和特定的功能 并表征了免疫细胞中MA和CMA的老化相关失调。该获取的 知识、既定工具和获得的专业知识使我们能够更好地了解新的 在老年科学的背景下的重要概念-具体来说，定义如何改变两个之间的相互作用 器官系统，免疫系统和中枢神经系统，促进失调的传播， 自噬介导的蛋白质稳态网络，并导致年龄相关的病理。 在这个项目中，我们将研究衰老的造血和外周免疫功能的后果， 系统与受损的AD蛋白稳态，以及表征AD对免疫细胞的相互作用 产生和作用。我们将确定T细胞中蛋白质稳态改变的后果， 阿尔茨海默病（Aim 1）的发展和进展，表征年龄相关自噬的作用- 先天性免疫细胞缺陷起源于常见的获得性克隆造血， 神经退行性变和老年性痴呆（Aim2），并阐明如何AD相关的蛋白毒性有助于 骨髓和外周免疫细胞（Aim3）中的功能失调和蛋白质稳态， PP中的整合：该项目将利用新型CMA报告小鼠，开发新的小鼠模型， 调节T细胞中的自噬以评估改善T细胞中的蛋白质稳态对于AD病理学的后果， 并建立和测试新的AD小鼠模型，该模型含有自噬受损的先天免疫细胞， 形成与年龄相关的克隆造血。我们还将使用AD的三种实验小鼠模型。所有 小鼠将由动物中心维护，并由所有项目共享。重要的是，我们将利用化学 由Therapeutics Core开发的CMA调节剂，以评估其恢复免疫功能的能力， 抑制或减缓神经变性和AD病理进展。基于图像的变化分析 外周和中枢自噬以及体内免疫细胞功能的评估将用 艺术图像技术提供的图像核心。外围设备与 将结合P1和P4研究中枢自噬，以及脑引流淋巴液的能力。 将与P2一起研究携带的产品对免疫细胞功能的影响。生物统计股将 协助分析数据和整合所有四个项目的结果。 与公共卫生的相关性：我们的研究将确定触发造血和外周血细胞改变的机制。 老年人的免疫功能，并为组织的系统关系提供新的基本见解， 老化过程中的退化。此外，本文收集的数据很可能提供强的临床前研究。 通过恢复自噬来开发用于年龄相关病理的新型治疗干预的基本原理。

Functional changes in both adaptive and innate immunity contribute to immunosenescence during aging. The immune system has also been implicated in inflammation, autoimmunity and reduced protein aggregate clearance in the brains of patients with Alzheimer’s disease (AD). Aging immune cells harbor wide-ranging impairment of autophagy pathways, including macroautophagy (MA) and chaperone-mediated autophagy (CMA), which trigger functional alterations in key immune cell subsets, such as T cells and monocyte-derived macrophages. Mechanisms responsible for the aging-associated decrease in autophagic activity and a comprehensive characterization of their functional consequences has remained elusive, but may hold the key for the development of innovative new therapies to counteract aging-associated neurodegenerative processes and pathologies, including AD and AD related dementias. In previous periods of this PP, we have identified new and specific functions of autophagy in the immune system and have characterized aging-associated dysregulation of MA and CMA in immune cells. This acquired knowledge, established tools and gained expertise allows us to now work towards a better understanding of new important concepts in the context of Geroscience – specifically, to define how an altered interplay between two organ systems, the immune system and the central nervous system, facilitates propagation of dysregulated autophagy-mediated proteostasis networks and leads to age-associated pathologies. In this project, we will investigate the functional consequences of an aging hematopoietic and peripheral immune system with impaired proteostasis in AD, as well as characterize the reciprocal effects of AD on immune cell generation and function. We will determine the consequences of altered proteostasis in T cells in the development and progress of Alzheimer’s disease (Aim1), characterize the role of age-associated autophagy- defective innate immune cells originating from commonly occurring acquired clonal hematopoiesis in neurodegeneration and AD during aging (Aim2) and elucidate how AD-associated proteotoxicity contributes to the dysregulation of function and proteostasis in the bone marrow and peripheral immune cells (Aim3), Integration in the PP: This project will utilize novel CMA reporter mice, develop new mouse models with modulated autophagy in T cells to assess the consequences of improve proteostasis in T cells for AD pathology, and establish and test novel AD mouse models harboring autophagy-impaired innate immune cells originating form age-associated clonal hematopoiesis. We will also use the three experimental mouse models of AD. All mice will be maintained by the Animal Core and shared by all the projects. Importantly, we will utilize chemical modulators of CMA developed by Therapeutics Core to evaluate their ability to restore immune function and inhibit or slow progress of neurodegeneration and AD pathology. Image-based analysis of the changes in peripheral and central autophagy and assessment of in vivo immune cell function will be done with state-of-the- art image technology provided by the Image Core. Mechanisms of intercommunication between peripheral and central autophagy will be investigated in conjunction with P1 and P4, and the ability of brain-draining lymph carried products to influence immune cell function will be studied together with P2. The Biostatistics Unit will assist with analysis of data and integration of results from all four projects. Relevance to public health: Our study will identify mechanisms triggering altered hematopoiesis and peripheral immune function in the elderly and provide novel fundamental insights into the systemic relationships of tissue degeneration during aging. Moreover, the data collected herein are very likely to provide strong preclinical rationales for developing novel therapeutic interventions for age-associated pathologies by restoring autophagy.