Long Non-coding RNA Regulation in Astrocytes within the Aging Brain

衰老大脑中星形胶质细胞的长非编码RNA调控

• 批准号: 10602434
• 负责人: Farah Dominique Lubin
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602434
• 关键词: Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animal Model; Animals; Area; Astrocytes; Biological Models; Brain; CRISPR-mediated transcriptional activation; Calcium Signaling; Cell physiology; Cells; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Methylation; Data; Disease; Dorsal; Epigenetic Process; G9a histone methyltransferase; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Head; Hippocampus; Human; Hypermethylation; Intervention; J20 mouse; Knock-out; LoxP-flanked allele; Mediating; Memory; Memory Loss; Memory impairment; Molecular; Mus; Neuroglia; Neurons; Pathogenesis; Pilot Projects; Play; Population; Positioning Attribute; Process; Proteins; RNA; Regulation; Regulator Genes; Research; Role; Signal Transduction; System; Testing; Therapeutic; Tissue-Specific Gene Expression; Untranslated RNA; Vertebral column; Western Blotting; Work; age related; aged; aging brain; aging hippocampus; aging population; awake; behavior measurement; chromatin isolation by RNA purification sequencing; cohort; density; designer receptors exclusively activated by designer drugs; histone methylation; histone modification; insight; knock-down; normal aging; novel; overexpression; programs; promote resilience; promoter; research study; resilience; single nucleus RNA-sequencing; small hairpin RNA; transcription factor; transcriptome sequencing; young adult

Project Summary We propose to investigate the contribution of the long non-coding RNA (lncRNA) Neat1 in astrocytes and identify the epigenetic mechanisms in these glia cells involved in enhancing memory resiliency with age. Interventions to enhance memory resilience within the aging population are possible. However, research studies that inform resiliency in this area are still lacking. Within the aging hippocampus, it is now clear that abnormal epigenetic control of gene transcription contributes to memory deficits. Nearly all the suggested epigenetic mechanisms controlling memory formation have mostly been attributed to neuronal cells within the hippocampus, largely disregarding these mechanisms in astrocytes. Thus, little is known about how astrocytic epigenetic mechanisms influence memory resiliency with age. Our long-term goal is to study the role of lncRNAs in astrocytes and to identify how these powerful epigenetic regulators impact memory formation with aging. Our pilot data demonstrate that Neat1 expression is decreased in area CA1 of young adult mice and overexpressed in aged mice. Furthermore, we demonstrate that inhibiting Neat1 expression in area CA1 of the hippocampus of aged mice reverses memory impairments. Pilot studies also suggest a strong relationship between G9a mediated H3K9me2 hypermethylation with Neat1 overexpression in aged adults. Based on these preliminary results, we plan to rigorously investigate the effects of manipulating Neat1 in astrocytes and determine effects on age-related memory decline. To gain further mechanistic insight into Neat1 mediated gene transcription in astrocytes in the aging hippocampus, we will use state-of-the-art approaches such as CRISPR reprogramming and chemogenetics to elucidate the epigenetic mechanisms in astrocytes in our aging animal model system. Our overarching hypothesis is that Neat1 contributes to age-associated changes in hippocampal astrocyte diversity, astrocyte function and vulnerability to memory dysfunction. Our Specific Aims are as follows: Specific Aim 1: Test the hypothesis that Neat1 is associated with astrocyte diversity with aging; Specific Aim 2: To determine the mechanism by which Neat1 acts to influence chromatin restructuring in astrocytes from young versus aged animals; and Specific Aim 3: To determine the contribution of astrocytic Neat1 to memory resiliency with age. Collectively, these studies will identify epigenetic mechanisms in astrocytes involved in age-related memory decline, with broad implications for treatment options for age-related dementia and Alzheimer’s disease.

项目摘要 我们建议研究星形胶质细胞中长的非编码RNA（LNCRNA）Neat1的贡献 这些胶质细胞中的表观遗传机制涉及随着年龄的增强记忆弹性。 可以在衰老人群中提高记忆弹性的干预措施。但是，研究 该领域的弹性仍然缺乏。在海马衰老内，现在很明显 基因转录的表观遗传控制有助于记忆缺陷。几乎所有建议的表观遗传学 控制记忆形成的机制主要归因于海马内的神经元细胞， 在星形胶质细胞中很大程度上忽略了这些机制。关于星形胶质细胞表观遗传学的知之甚少 机制会影响记忆的弹性随着年龄的增长。我们的长期目标是研究lncrnas在 星形胶质细胞并确定这些强大的表观遗传调节剂如何通过衰老影响记忆形成。我们的 试验数据表明，年轻小鼠的CA1面积neat1表达降低，并且过表达 在老年小鼠中。此外，我们证明了抑制neat1表达在海马的海马区域 老年小鼠会逆转记忆力障碍。试点研究还表明G9A之间有很强的关系 老年成年人中介导的H3K9me2高甲基化含Neat1的过表达。基于这些初步 结果，我们计划严格研究操纵Neat1在星形胶质细胞中的影响，并确定效果 与年龄有关的记忆下降。为了进一步了解Neat1介导的基因转录 海马衰老的星形胶质细胞，我们将使用最先进的方法，例如CRISPR重新编程 和化学遗传学以阐明我们老化动物模型系统中星形胶质细胞中的表观遗传机制。我们的 总体假设是Neat1有助于与年龄相关的海马星形胶质细胞多样性变化， 星形胶质细胞功能和内存功能障碍的脆弱性。我们的具体目的如下：特定目标1： 检验Neat1与星形胶质细胞多样性随老化有关的假设；特定目标2：确定 Neat1会影响年轻人与年龄的星形胶质细胞中染色质餐厅的机制 动物;和特定目的3：确定星形胶质细胞Neat1随着年龄的增长的记忆弹性的贡献。 总的来说，这些研究将确定与年龄相关记忆的星形胶质细胞中的表观遗传机制 下降，对与年龄有关的痴呆和阿尔茨海默氏病的治疗选择具有广泛的影响。