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.

适应性和先天免疫的功能变化导致衰老过程中的免疫衰老。 免疫系统也与炎症、自身免疫和蛋白质聚集减少有关 阿尔茨海默病（AD）患者大脑中的衰老免疫细胞具有广泛的清除能力。 自噬途径受损，包括巨自噬 (MA) 和分子伴侣介导的自噬 (CMA)，触发关键免疫细胞亚群的功能改变，例如 T 细胞和单核细胞衍生的 巨噬细胞导致衰老相关的自噬活性下降的机制。 其功能后果的全面表征仍然难以捉摸，但可能是关键 开发创新疗法来对抗衰老相关的神经退行性过程 和病理学，包括 AD 和 AD 相关痴呆症。 在本 PP 的前几期中，我们已经确定了免疫系统中自噬的新的和特定的功能 并发现免疫细胞中与衰老相关的 MA 和 CMA 失调。 知识、既定工具和获得的专业知识使我们现在能够努力更好地理解新的 老年科学背景下的重要概念——具体来说，定义两者之间的相互作用 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与年龄相关的病理。 在这个项目中，我们将研究衰老的造血系统和外周免疫系统的功能后果 AD 中蛋白质稳态受损的系统，以及 AD 对免疫细胞的相互影响的特征 我们将确定 T 细胞中蛋白质稳态改变的后果。 阿尔茨海默氏病的发生和进展（Aim1），表征与年龄相关的自噬的作用 源自常见的获得性克隆造血的有缺陷的先天免疫细胞 衰老过程中的神经退行性变和 AD（目标 2），并阐明 AD 相关的蛋白质毒性如何导致 骨髓和外周免疫细胞的功能和蛋白质稳态失调（Aim3）， 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 细胞的自噬，以评估改善 T 细胞蛋白质稳态对 AD 病理学的影响， 建立并测试新型 AD 小鼠模型，该模型含有自噬受损的先天免疫细胞 我们还将使用三种 AD 实验小鼠模型。 小鼠将由动物核心维护并由所有项目共享，重要的是，我们将使用化学物质。 Therapeutics Core 开发的 CMA 调节剂，用于评估其恢复免疫功能的能力和 抑制或减缓神经退行性病变和 AD 病理学变化的图像分析。 外周和中枢自噬以及体内免疫细胞功能的评估将采用最新技术进行 Image Core提供的艺术图像技术与外设之间的互通机制。 将结合P1和P4研究中枢自噬，以及脑排空淋巴的能力 将与 P2 一起研究影响免疫细胞功能的携带产品。 协助分析数据并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 此外，本文收集的数据很可能提供强有力的临床前研究。 通过恢复自噬来开发针对与年龄相关的病理学的新型治疗干预措施的基本原理。