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

项目总结/摘要 无法形成和储存长期记忆是衰老和神经退行性变中认知能力下降的一个特征。 专家预测，从轻度到重度痴呆的认知障碍的患病率将增加 随着美国65岁及以上老年人人口的迅速增长， 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 老年大脑中记忆形成的机制，以制定早期干预策略， 老年人的认知功能正如我们实验室和其他实验室所观察到的，组蛋白去乙酰化酶3（HDAC 3）是一种强大的 记忆形成和突触可塑性的表观遗传调节因子。然而，调节HDAC 3的机制在 大脑老化与记忆力的关系还不清楚。新出现的数据表明HDAC 3可能是 在癌细胞中由上游激酶和磷酸酶调节，这使我假设磷酸化 HDAC 3的状态决定了HDAC 3调节记忆形成和突触可塑性的能力。 此外，HDAC 3磷酸化的机制在记忆过程中变得失调， 在老化的大脑中巩固，导致与年龄相关的记忆障碍。初步数据显示， 一项提案揭示了磷酸HDAC 3的基线水平在衰老小鼠（18个月）的海马体中降低 与年轻的成年小鼠（3个月）相比。此外，我开发了HDAC 3突变病毒构建体，以测试 磷酸化HDAC 3（磷酸模拟）和去磷酸化HDAC 3（磷酸无效）在记忆中的功能 形成和突触可塑性在年轻的成年人和老龄化的大脑。初步结果表明， HDAC 3磷酸模拟物的表达损害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HDAC 3磷酸化缺失的表达改善了与年龄相关的记忆障碍。 形成和突触可塑性。总之，这些发现表明HDAC 3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，本建议将重点放在 继续研究HDAC 3磷酸化对成年人记忆形成的表观遗传调节， 和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 HDAC 3磷酸化在年轻成人大脑中的作用;目标2，确定HDAC 3磷酸化的作用 目的3，确定HDAC 3磷酸化调节记忆的机制 年轻人和老年人大脑的形成。该项目的发现可能会阐明一种新的 HDAC 3在记忆中的表观遗传调节机制，可以对所有衰老产生根本影响 有认知障碍的人。这项培训奖学金将允许发展分子， 生理学和生物信息学专业知识。在伍德博士的指导下， 在UCI的环境，这个奖学金将提供一个成功的职业生涯作为一个独立的调查员的基础 专注于理解衰老大脑中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.