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

项目摘要 我们建议研究长链非编码RNA（lncRNA）Neat 1在星形胶质细胞中的作用，并鉴定 这些神经胶质细胞中的表观遗传机制与随着年龄的增长增强记忆弹性有关。 干预措施，以提高老年人口的记忆恢复力是可能的。然而，研究表明， 这一领域仍然缺乏知情复原力。在老化的海马体中，现在很明显， 基因转录的表观遗传控制导致记忆缺陷。几乎所有的表观遗传学 控制记忆形成的机制主要归因于海马体内的神经元细胞， 很大程度上忽略了星形胶质细胞中的这些机制。因此，很少有人知道星形胶质细胞表观遗传 机制随着年龄的增长影响记忆弹性。我们的长期目标是研究lncRNA在 星形胶质细胞，并确定这些强大的表观遗传调节因子如何影响衰老的记忆形成。我们 初步数据表明，Neat 1在年轻成年小鼠的CA 1区表达减少， 老年小鼠此外，我们证明，抑制Neat 1在海马CA 1区的表达， 老年小鼠逆转记忆障碍。初步研究还表明，G9 a与 介导的H3 K9 me 2高甲基化和Neat 1过表达。基于这些初步 结果，我们计划严格调查在星形胶质细胞中操纵Neat 1的影响，并确定其影响。 与年龄相关的记忆力衰退为了进一步了解Neat 1介导的基因转录机制， 老化海马中的星形胶质细胞，我们将使用最先进的方法，如CRISPR重编程 和化学遗传学来阐明我们衰老动物模型系统中星形胶质细胞的表观遗传机制。我们 最重要的假设是Neat 1有助于海马星形胶质细胞多样性的年龄相关变化， 星形胶质细胞功能和记忆功能障碍的脆弱性。我们的具体目标如下：具体目标1： 检验Neat 1与衰老星形胶质细胞多样性相关的假设;具体目标2：确定 Neat 1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Neat 1对随年龄增长的记忆恢复力的贡献。 总的来说，这些研究将确定参与年龄相关记忆的星形胶质细胞的表观遗传机制 下降，对年龄相关性痴呆和阿尔茨海默病的治疗选择具有广泛的影响。

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.