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

项目 3 - 衰老和年龄相关疾病中造血和外周免疫功能以及自噬的失调

• 批准号: 10397012
• 负责人: Fernando Macian
• 金额: $ 63.84万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397012
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animals; Attenuated; Autoimmunity; Automobile Driving; Autophagocytosis; Biometry; Bone Marrow; Brain; Brain Drains; Cardiovascular Diseases; Cell Compartmentation; Cell physiology; Cells; Chemicals; Cues; Data; Data Analyses; Defect; Dementia; Deterioration; Development; Disease; Elderly; Epigenetic Process; Erythroid Progenitor Cells; Functional disorder; Generations; Genetic; Geroscience; Growth; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Image; Imaging technology; Immune; Immune system; Immunity; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Lesion; Lymph; Lymphoid Cell; Mediating; Molecular Chaperones; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Nerve Degeneration; Neuraxis; Normal Cell; Organ; Organism; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral; Population; Process; Public Health; Recycling; Regulation; Reporter; Role; Stress; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Work; adaptive immunity; age related; aging brain; base; body system; brain cell; data integration; functional restoration; hematopoietic differentiation; immune function; immunosenescence; improved; in vivo; inflammatory modulation; innovation; insight; macrophage; mind control; monocyte; mouse model; neuroinflammation; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; precursor cell; prevent; progenitor; protein aggregation; proteostasis; proteotoxicity; restoration; stem cells; therapeutic target; tissue degeneration; tool

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.

适应性免疫和先天免疫的功能变化导致了衰老过程中的免疫衰老。这个 免疫系统也与炎症、自身免疫和蛋白质聚集体减少有关。 阿尔茨海默病(AD)患者大脑中的清除。老化的免疫细胞藏匿于广泛的 自噬途径受损，包括巨噬(MA)和伴侣介导的自噬 (CMA)，触发关键免疫细胞亚群的功能变化，如T细胞和单核细胞来源 巨噬细胞。与衰老相关的自噬活性下降的机制和 对它们的功能后果的全面描述仍然难以捉摸，但可能掌握着关键 用于开发创新的新疗法以对抗与衰老相关的神经退化过程 和病理学，包括阿尔茨海默病和阿尔茨海默病相关痴呆。 在这个PP的前几个阶段，我们已经确定了免疫系统中自噬的新的和特定的功能 并表征了与衰老相关的免疫细胞中MA和CMA的调节失调。这是获得的 知识、成熟的工具和获得的专业知识使我们现在能够更好地理解新的 老年科学背景下的重要概念-具体地说，定义两个 器官系统，免疫系统和中枢神经系统，促进失调的传播 自噬介导的蛋白平衡网络，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的功能后果。 阿尔茨海默病中蛋白平衡受损的系统以及AD对免疫细胞的相互作用 生成和功能。我们将确定T细胞蛋白平衡改变的后果 阿尔茨海默病(Aim1)的发展和进展，表征了年龄相关自噬的作用- 源于常见获得性克隆性造血的先天免疫细胞缺陷 神经退行性变和衰老中的阿尔茨海默病(AIM2)，并阐明AD相关的蛋白毒性是如何在 骨髓和外周免疫细胞的功能和蛋白平衡失调(Aim3)， PP中的整合：该项目将利用新的CMA报告小鼠，开发新的鼠标模型 调节T细胞自噬以评估改善T细胞蛋白稳定性对AD病理的影响 并建立和测试新型AD小鼠模型，该模型含有自噬受损的先天性免疫细胞，源于 形成与年龄相关的克隆性造血。我们还将使用AD的三个实验性小鼠模型。全 MICE将由动物核心组织维护，并由所有项目共享。重要的是，我们将使用化学物质 由Treateutics Core开发的CMA调节剂用于评估其恢复免疫功能和 抑制或减缓神经退行性变和AD病理的进展。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在以下情况下完成- 艺术影像技术由影像核心提供。外设和外设之间的互通机制 中枢自噬将与P1和P4一起研究，以及脑淋巴引流的能力 携带的影响免疫细胞功能的产品将与P2一起研究。生物统计股将 协助分析所有四个项目的数据和整合结果。 与公众健康的相关性：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，为组织的系统关系提供了新的基本见解 衰老过程中的退化。此外，这里收集的数据很可能提供强大的临床前 通过恢复自噬来开发针对年龄相关病理的新的治疗干预措施的理论基础。