Identifying signatures of brain aging through heterochronic blood exchange

通过异时血液交换识别大脑衰老的特征

• 批准号: 10408097
• 负责人: Irina M Conboy
• 金额: $ 46.9万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408097
• 关键词: Affect; Age; Aging; Amino Acids; Animals; Anti-Inflammatory Agents; Array tomography; Attenuated; Behavior; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; Cells; Chronic; Cognition; Data; Defect; Dendritic Spines; Disease; Dissection; Drug or chemical Tissue Distribution; Excitatory Synapse; Exhibits; Health; Hippocampus (Brain); Homeostasis; Human; Image; Imaging Techniques; Immune; Immune response; Impaired cognition; Impairment; Individual; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Interleukin-1 beta; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-6; Lead; Life Expectancy; Literature; Living Standards; Mediating; Mediator of activation protein; Microglia; Modern Medicine; Modernization; Molecular; Molecular Profiling; Morphology; Mus; Nerve Degeneration; Neuraxis; Neurodevelopmental Disorder; Neuroimmune; Neurons; Oxytocin; Parabiosis; Pattern; Peptides; Peripheral; Pharmaceutical Preparations; Physiological; Population; Process; Proteins; Proteome; Proteomics; Publishing; Research; Resolution; Signal Pathway; Signal Transduction; Site; Societies; Somatosensory Cortex; Structure; Surgical sutures; Synapses; TNF gene; Testing; Therapeutic Effect; Tissues; Transforming Growth Factor beta; Vertebral column; Work; aged; aging brain; brain cell; brain health; cell motility; cognitive function; cytokine; experimental study; frontal lobe; functional decline; hippocampal pyramidal neuron; imaging modality; improved; in vivo; in vivo two-photon imaging; inhibitor; juvenile animal; nervous system development; neural circuit; neurogenesis; neuroinflammation; normal aging; postsynaptic; potential biomarker; prevent; protein expression; reconstruction; response; therapeutic evaluation; tissue repair; two photon microscopy

Project Summary The improvement in living standards and the advancement in modern medicine have greatly extended human life expectancy. However, aging-related functional decline and diseases, in particular cognitive impairment and neurodegeneration, also become more prevalent. Studies of heterochronic blood exchange reveal that the aged systemic milieu inhibits neurogenesis and impairs cognitive functions in young animals, suggesting the existence of age-elevated systemic factors detrimental to brain health. In particular, inflammation may become excessive and chronic with aging (“inflammaging”) and impair normal brain functions. Thus proteins involved in inflammatory responses, such as cytokines, are candidates of such systemic factors implicated in brain aging. Building upon published literature and our recent finding, we hypothesize that aging-associated alterations in systemic inflammatory factors activate microglia (resident immune cells in the central nervous system) and lead to microglia-mediated synapse loss; restoring the expression pattern of such factors to the healthy young state rescues synaptic defects and improves cognitive functions. In Aim 1, we will use bio-orthogonal non- canonical amino acid tagging (BONCAT) to determine how treatment with a cocktail of Alk5 inhibitor (Alk5i) and oxytocin (OT, a neurotrophic, anti-inflammatory peptide) or heterochronic blood exchange affects the expression profile and distribution of inflammaging-related systemic factors in the brain and peripheral tissues. Aim 2 examines how Alk5i+OT treatment and heterochronic blood exchange affect neuro-immune interaction in the brain, taking advantage of in vivo two-photon imaging to study microglia-synaptic interactions and their effects on synaptic integrity and dynamics in the cortex. Using Array Tomography, a high-throughput, super- resolution proteomic imaging technique, Aim 3 conducts molecular dissection and reconstruction of large populations of individual synapses and determines the effect of Alk5i+OT treatment and heterochronic blood exchange on synaptic molecular signatures and inflammatory cytokine distribution in the brain. Together, these studies will provide a comprehensive characterization of age-specific effects of blood on the brain proteome and synaptic circuits, and outline candidate mechanism(s) responsible for brain aging.

项目摘要 生活水平和现代医学进步的改善具有巨大的扩展人类 预期寿命。但是，与衰老相关的功能下降和疾病，特别是认知障碍和 神经变性也变得更加普遍。异缘血液交换的研究表明 老年系统环境抑制神经发生并损害年轻动物的认知功能，表明 年龄高度的系统因素的存在不利于大脑健康。特别是，感染可能成为 过度和慢性衰老（“炎症”）并损害正常的大脑功能。参与的蛋白质 炎症反应（例如细胞因子）是大脑衰老中实施的这种系统性因素的候选者。 在出版的文献和我们最近的发现的基础上，我们假设与衰老相关的变化 全身性炎症因子激活小胶质细胞（中枢神经系统中的居民免疫核管）和 导致小胶质细胞介导的突触损失；恢复健康年轻人的这些因素的表达模式 国家救援会突触缺陷并改善认知功能。在AIM 1中，我们将使用生物正交的非 - 规范氨基酸标记（Boncat）确定如何用ALK5抑制剂鸡尾酒（ALK5I）治疗 和氧毒素（OT，神经营养，抗炎肽）或异缘血液交换会影响 脑和周围组织中与炎症相关的全身因子的表达谱和分布。 AIM 2考试ALK5I+OT治疗和异缘血液交换如何影响神经免疫相互作用 在大脑中，利用体内两光子成像研究小胶质细胞突触相互作用及其 对皮质中合成完整性和动力学的影响。使用阵列层析成像，高通量，超级 分辨率蛋白质组学成像技术，AIM 3进行分子解剖和重建大型 个体突触的种群，并确定ALK5I+OT治疗和异缘血液的影响 交换大脑中的合成分子特征和炎症细胞因子分布。在一起，这些 研究将为血液对脑蛋白质组的年龄特异性影响提供全面的表征 和突触电路，并概述负责大脑衰老的候选机制。