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

基本信息

批准号：
10196771
负责人：
Irina M Conboy
金额：
$ 49.91万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
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/10196771
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/antagonist 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

项目摘要

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.

项目概要生活水平的提高和现代医学的进步极大地扩展了人类然而，与衰老相关的功能衰退和疾病，特别是认知障碍和异时性血液交换的研究表明，神经退行性疾病也变得更加普遍。老化的系统环境会抑制幼年动物的神经发生并损害认知功能，这表明随着年龄的增长，系统性因素的存在可能会影响大脑健康，尤其是炎症。过度和慢性老化（“炎症”）并损害正常的大脑功能，因此参与蛋白质。细胞因子等炎症反应是与大脑衰老有关的系统性因素的候选者。根据已发表的文献和我们最近的发现，我们帮助研究了与衰老相关的变化全身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丧失；恢复健康年轻人的这些因子的表达模式；状态挽救突触缺陷并改善认知功能在目标 1 中，我们将使用生物正交非-。规范氨基酸标签 (BONCAT) 以确定如何使用 Alk5 抑制剂混合物 (Alk5i) 进行治疗催产素（OT，一种神经营养性抗炎肽）或异时性血液交换会影响大脑和周围组织中炎症相关全身因子的表达谱和分布。目标 2 检查 Alk5i+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来研究小胶质细胞-突触相互作用及其使用阵列断层扫描（一种高通量、超强）对皮质突触完整性和动态的影响。分辨率蛋白质组成像技术，Aim 3 进行大分子解剖和重建个体突触群体并确定 Alk5i+OT 治疗和异时血液的效果大脑中突触分子特征和炎症细胞因子分布的交换。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，并概述导致大脑衰老的候选机制。