Reversing age-related epigenetic changes and characterizing microglia heterogeneity in obesity and aging

逆转与年龄相关的表观遗传变化并表征肥胖和衰老中的小胶质细胞异质性

基本信息

批准号：
10562551
负责人：
Victor Afriyie Ansere
金额：
$ 3.71万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10562551
关键词：
Address Affect Affinity Chromatography Age Aging Animals BODIPY Bioinformatics Biological Assay Biology Blood Volume Brain Caloric Restriction Cell Nucleus Cells Communication DNA DNA Methylation DNA Modification Process Data Development Disease Elderly Elements Enhancers Epigenetic Process Fatty acid glycerol esters Fluorescence-Activated Cell Sorting Foundations Functional disorder Future Gene Expression Genes Genomics Goals Grant Heterogeneity High Fat Diet Hippocampus (Brain)Impairment Inflammation Inflammatory Intervention Knowledge Laboratories Life Lipids Maintenance Manuscripts Mentors Messenger RNA Methylation Microglia Modeling Molecular Morphology Mus Neurodegenerative Disorders Nuclear Nutritional Obese Mice Obesity Operative Surgical Procedures Oral Pathologic Pattern Phagocytes Phase Phenotype Physiological Plasma Population RNA Research Ribosomes Role Saline Scientist Site Structure Technical Expertise Techniques Technology Testing Thinness Tissues Training Translating Writing age group age related aging brain anti aging base bisulfite sequencing career cell type chemokine cytokine design diet-induced obesity dietary epigenome epigenome editing epigenomics experience functional decline immune activation improved innovation insight interest laboratory experience macrophage molecular phenotype mouse model neuroinflammation novel strategies prevent response sex single-cell RNA sequencing skills systemic inflammatory response transcriptome sequencing transcriptomics translational study translatome uptake whole genome

项目摘要

Project Summary Neuroinflammation is a hallmark of brain aging that may contribute to declines in function and neurodegenerative diseases. As the resident macrophage of the brain, microglial are crucial to brain maintenance but have been demonstrated to take on pro-inflammatory phenotypes with aging. The proposed research will examine the role of microglia-specific epigenetic mechanisms in aging and determine the effects of obesity and aging interactions on microglia phenotypic heterogeneity. We will determine whether aberrant age-related microglia-specific epigenetic patterns can be reversed by heterochronic plasma approaches. Additionally, we will determine how microglia subpopulations differ with age and obesity at a single-cell level with special interests in lipid-droplet- accumulating microglia (LDAM). The goals of the training are to: 1) obtain a strong knowledge and foundation in animal and nutritional models of anti-aging and obesity 2) gain hands-on experience in technologies and bioinformatic skills needed for various omics approaches in specific hippocampal cells and at a single-cell level 3) apply these skills to achieve the research aims outlined in this proposal and 5) gain experience and improve oral and presentation skills, manuscript and grant writing to enable a transition to independence. In Aim 1, we hypothesize that exposure of old mice to young plasma will reverse age-related microglia-specific DNA modifications to restore ‘youthful’ epigenomic patterns. This is based on the premise that DNA modifications are key regulators of the diverse phenotypes required for the fulfillment of microglia functions which are disrupted in aging. We will determine whether the administration of plasma from young into old mice can reverse age-related microglial-specific hippocampal epigenetic and transcriptomic changes in Cx3cr1:NuTRAP mice using whole genome oxidative bisulfite sequencing (WGoxBS) and RNA sequencing, respectively. These studies will identify specific genomic sites amenable to the rejuvenating interventions and serve as targets for future epigenome editing studies. In Aim 2, we will determine how the interaction of obesity and aging affect microglia heterogeneity. We hypothesize that high-fat diet leads to expansion of pathological LDAM resulting in impaired microglial function, which can be reversed by late-life calorie restriction. We will use single-cell transcriptomic analysis, bulk transcriptomics and microglia functional assays (phagocytic uptake and cytokine/chemokine analysis) to determine changes in microglia subpopulations in dietary-induced obese mice with age. In addition, we will determine whether starting calorie restriction at 12 months in dietary-induced obese mice can mitigate the effects of obesity on microglia heterogeneity. This will help identify mechanistic insights into microglia heterogeneity, LDAM and obesity-associated neuroinflammation. In total, the training goals and objectives will provide the needed skills and expertise to pursue a research career focused on developing anti-aging interventions.

项目概要神经炎症是大脑衰老的标志，可能导致功能下降和神经退行性病变作为大脑中常驻的巨噬细胞，小胶质细胞对于大脑的维护至关重要，但一直以来都被忽视。呈现随衰老而表现出的促炎表型。拟议的研究将检验其作用。研究衰老过程中小胶质细胞特异性表观遗传机制，并确定肥胖和衰老相互作用的影响我们将确定小胶质细胞表型异质性是否与年龄相关。此外，表观遗传模式可以通过异时等离子体方法逆转。小胶质细胞亚群在单细胞水平上随年龄和肥胖程度的不同而不同，对脂滴特别感兴趣累积小胶质细胞（LDAM）的培训目标是：1）获得扎实的知识和基础。抗衰老和肥胖的动物和营养模型 2) 获得技术和实践方面的实践经验特定海马细胞和单细胞水平的各种组学方法所需的生物信息技能 3) 应用这些技能来实现本提案中概述的研究目标，5) 获得经验并改进口头和演讲技巧、手稿和资助写作，以实现向独立的过渡。在目标 1 中，我们。越来越多的证据表明，年老小鼠接触年轻小鼠血浆会逆转与年龄相关的小胶质细胞特异性 DNA 恢复“年轻”表观基因组模式的修饰是基于 DNA 修饰是的前提。实现小胶质细胞功能所需的多种表型的关键调节因子，这些功能在我们将确定将年轻小鼠的血浆注射到老年小鼠体内是否可以逆转与年龄相关的衰老。使用全细胞研究 Cx3cr1:NuTRAP 小鼠中小胶质细胞特异性海马表观遗传和转录组变化这些研究将分别鉴定基因组氧化亚硫酸氢盐测序（WGoxBS）和RNA测序。特定的基因组位点适合复兴干预措施并作为未来表观基因组的目标在目标 2 中，我们将确定肥胖和衰老的相互作用如何影响小胶质细胞。我们发现高脂肪饮食会导致病理性 LDAM 扩张，从而导致受损。小胶质细胞功能，可以通过晚年热量限制来逆转我们将使用单细胞转录组学。分析、大量转录组学和小胶质细胞功能测定（吞噬细胞摄取和细胞因子/趋化因子分析）以确定饮食诱导的肥胖小鼠中小胶质细胞亚群随年龄的变化。我们将确定在 12 个月时开始限制饮食引起的肥胖小鼠的热量是否可以缓解肥胖对小胶质细胞异质性的影响这将有助于识别小胶质细胞的机制。异质性、LDAM 和肥胖相关的神经炎症总的来说，培训目标和目标将。提供所需的技能和专业知识，以从事专注于开发抗衰老的研究事业干预措施。