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 生活水平的提高和现代医学的进步极大地延长了人类的寿命 预期寿命然而，与衰老有关的功能衰退和疾病，特别是认知障碍和 神经变性也变得更加普遍。异时血液交换的研究表明， 老年全身环境抑制神经发生并损害年轻动物的认知功能，这表明 存在对大脑健康有害的年龄升高的全身性因素。特别是，炎症可能会成为 过度和慢性老化（“炎症”），并损害正常的脑功能。因此，蛋白质参与 炎性反应如细胞因子是与脑老化有关的系统性因素的候选者。 基于已发表的文献和我们最近的发现，我们假设， 全身性炎症因子激活小胶质细胞（中枢神经系统中的常驻免疫细胞）， 导致小胶质细胞介导的突触丢失;恢复健康年轻人这些因子的表达模式 国家挽救突触缺陷和改善认知功能。在目标1中，我们将使用生物正交非 典型氨基酸标记（BONCAT），以确定如何用Alk 5抑制剂（Alk 5i）的混合物治疗 和催产素（OT，一种神经营养抗炎肽）或异时血液交换影响 炎症相关系统因子在脑和外周组织中的表达谱和分布。 目的2检查Alk 5i +OT治疗和异时血液交换如何影响神经免疫相互作用 在大脑中，利用体内双光子成像研究小胶质细胞-突触相互作用及其 对皮层中突触完整性和动力学的影响。使用阵列断层扫描，一个高通量，超- 分辨率蛋白质组成像技术，目的3进行分子解剖和重建大的 图1显示了单个突触的群体，并确定了Alk 5i +OT处理和异时血液刺激的效果。 突触分子标记和炎性细胞因子在脑中的分布的交换。所有这些 研究将提供血液对大脑蛋白质组的年龄特异性影响的全面表征 和突触回路，并概述了负责大脑老化的候选机制。