Investigating HDAC3 phosphorylation as an epigenetic regulator of memory formation in the adult and aging brain

项目摘要/摘要 未能形成和储存长期记忆是衰老和神经退化过程中认知能力下降的一个特征。 专家预测，从轻度到重度痴呆症的认知障碍患病率将会增加 随着美国65岁及以上老年人口的快速增长，给 为老年人提供资源和照顾。有必要了解表观遗传学和分子生物学 衰老大脑中记忆形成的机制以制定早期干预策略和保存 老年时的认知功能。正如我们实验室和其他实验室观察到的那样，组蛋白脱乙酰基酶3(HDAC3)是一种强大的 记忆形成和突触可塑性的表观遗传调节。然而，调控HDAC3的机制在 关于记忆的老化大脑仍然没有明确的定义。新出现的数据表明，HDAC3可能是 在癌细胞中由上游的激酶和磷酸酶调节，这让我假设 HDAC3的状态决定了HDAC3调节记忆形成和突触可塑性的能力。 此外，在记忆过程中，HDAC3的磷酸化机制变得失调 老化的大脑中的固结，导致与年龄相关的记忆损伤。本报告中的初步数据 一项提案显示，衰老小鼠(18个月)的海马区磷酸化HDAC3的基线水平降低。 与幼年成年小鼠(3个月)相比。此外，我开发了HDAC3突变病毒构建物来测试 磷酸化HDAC3(模拟磷酸化)和去磷酸化HDAC3(零磷酸化)在记忆中的作用 青壮年和老年脑的形成和突触可塑性。初步结果表明，病毒 HDAC3磷酸化模拟蛋白的表达损害了年轻成年小鼠的记忆形成和突触可塑性。 然而，在衰老小鼠中表达HDAC3磷酸零可以改善与年龄相关的记忆损害 形成和突触可塑性。总之，这些发现表明，HDAC3的磷酸化是一种机制 可以动态调节长期记忆和突触功能。因此，这项提案将重点放在 继续研究HDAC3磷酸化对成人记忆形成的表观遗传调节 以及老化的男性和女性大脑。本提案中的具体目标将确定以下内容：目标1，确定 HDAC3磷酸化在青壮年脑中的作用；目的2，确定HDAC3磷酸化的作用 在老化的大脑中；目标3，确定HDAC3磷酸化调节记忆的机制 在青壮年和衰老的大脑中形成。这个项目的发现可能会阐明一部小说 记忆中HDAC3表观遗传调控的机制可能对所有衰老产生根本影响 有认知障碍的人。这一培训奖学金将允许开发分子， 生理学和生物信息学专业知识。在伍德博士的指导下，研究和专业人士 在UCI的环境，这一奖学金将为成功的独立调查员职业生涯奠定基础 专注于了解老化大脑中潜在的学习和记忆的表观遗传机制。

Project Summary/Abstract Failure to form and store long-term memories is a feature of cognitive decline in aging and neurodegeneration. Experts predict that the prevalence of cognitive impairment, ranging from mild to severe dementia, will increase alongside the rapidly growing U.S. population of older adults aged 65 and older, creating new challenges to provide resources and care for older adults. There is a need to understand the epigenetic and molecular mechanisms of memory formation in the aging brain to develop early intervention strategies and preserve cognitive function in old age. As observed in our lab and others, histone deacetylase 3 (HDAC3) is a powerful epigenetic regulator of memory formation and synaptic plasticity. However, mechanisms regulating HDAC3 in the aging brain with regards to memory remain undefined. Emerging data suggesting that HDAC3 may be regulated in cancer cells by upstream kinases and phosphatases led me to hypothesize that the phosphorylation state of HDAC3 determines the ability of HDAC3 to regulate memory formation and synaptic plasticity. Furthermore, that the mechanism of HDAC3 phosphorylation becomes dysregulated during memory consolidation in the aging brain, contributing to age-related memory impairments. Preliminary data in this proposal reveals that baseline levels of phospho-HDAC3 are reduced in the hippocampus of aging mice (18-mo) compared to young adult mice (3-mo). Additionally, I developed HDAC3 mutant viral constructs to test the function of phosphorylated HDAC3 (phospho-mimic) and de-phosphorylated HDAC3 (phospho-null) in memory formation and synaptic plasticity in the young adult and aging brain. Preliminary results demonstrate that viral expression of the HDAC3 phospho-mimic impairs memory formation and synaptic plasticity in young adult mice. However, expression of the HDAC3 phospho-null in aging mice ameliorated age-related impairments in memory formation and synaptic plasticity. Together, these findings suggest that HDAC3 phosphorylation is a mechanism that can dynamically regulate long-term memory and synaptic function. Therefore, this proposal will focus on continuing to investigate the epigenetic regulation of HDAC3 phosphorylation on memory formation in the adult and aging male and female brain. Specific aims within this proposal will determine the following: Aim 1, determine the role of HDAC3 phosphorylation in the young adult brain; Aim 2, determine the role of HDAC3 phosphorylation in the aging brain; Aim 3, determine the mechanism by which HDAC3 phosphorylation regulates memory formation in the young adult and aging brain. Findings from this project will potentially elucidate a novel mechanism of HDAC3 epigenetic regulation in memory that can have a fundamental impact for all aging individuals with cognitive impairments. This training fellowship will allow for development of molecular, physiology and bioinformatics expertise. With the guidance of Dr. Wood and the research and professional environment at UCI, this fellowship will provide a foundation for successful career as an independent investigator focused on understanding the epigenetic mechanisms underlying learning and memory in the aging brain.