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: 10392421
• 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/10392421
• 关键词: Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; Area; Astrocytes; Biological Models; Brain; CRISPR-mediated transcriptional activation; Calcium Signaling; Cell Nucleus; Cell physiology; Cells; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Methylation; Data; Dementia; Disease; Dorsal; Epigenetic Process; G9a histone methyltransferase; Gene Expression; Genes; Genetic Transcription; Goals; Head; Hippocampus (Brain); 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; Small Nuclear RNA; System; Testing; Therapeutic; Tissue-Specific Gene Expression; Untranslated RNA; Vertebral column; Western Blotting; Work; age related; aged; aging brain; aging hippocampus; aging population; awake; base; 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; promoter; research study; resilience; 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 我们建议研究长非编码RNA(LncRNA)Neat1在星形胶质细胞中的作用并鉴定 这些胶质细胞的表观遗传机制涉及随着年龄的增长增强记忆弹性。 在老龄化人口中加强记忆韧性的干预措施是可能的。然而，研究研究 这一领域的复原力仍然不足。在老化的海马体内，现在很明显，异常 基因转录的表观遗传控制导致了记忆缺陷。几乎所有提出的表观遗传学 控制记忆形成的机制大多归因于海马体内的神经细胞， 在很大程度上忽略了星形胶质细胞的这些机制。因此，我们对星形细胞的表观遗传学知之甚少 随着年龄的增长，机制会影响记忆的弹性。我们的长期目标是研究lncRNAs在 并确定这些强大的表观遗传调节因子如何随着年龄的增长影响记忆的形成。我们的 初步数据显示，在幼年小鼠的CA1区，Neat1的表达减少，而在CA1区过表达 在衰老的小鼠身上。此外，我们还证明了抑制大鼠海马区CA1区Neat1的表达 衰老的小鼠可以逆转记忆损伤。初步研究还表明，G9a与 老年人群中H3K9me2高甲基化伴随Neat1过度表达基于这些初步的 结果，我们计划严格研究操纵星形胶质细胞中的Neat1的影响，并确定影响 与年龄相关的记忆力下降。为了进一步深入了解Neat1介导的基因转录 在老化的海马体中，我们将使用最先进的方法，如CRISPR重新编程 和化学遗传学，以阐明在我们的衰老动物模型系统中星形胶质细胞的表观遗传机制。我们的 最重要的假设是，Neat1有助于年龄相关的海马星形胶质细胞多样性的变化， 星形胶质细胞功能和对记忆功能障碍的易感性。我们的具体目标如下：具体目标1： 验证Neat1与星形胶质细胞多样性随年龄增长相关的假设；具体目标2：确定 Neat1影响年轻与老年星形胶质细胞染色质重组的机制 具体目标3：确定星形胶质细胞NEAT1对记忆随年龄增长的弹性的贡献。 总的来说，这些研究将确定星形胶质细胞参与年龄相关记忆的表观遗传机制。 下降，对老年痴呆症和阿尔茨海默病的治疗选择具有广泛的影响。