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

研究 HDAC3 磷酸化作为成人和衰老大脑记忆形成的表观遗传调节剂

• 批准号: 10752404
• 负责人: Alyssa Crystal Rodriguez
• 金额: $ 4.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752404
• 关键词: ATAC-seq; Address; Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; American; Bioinformatics; Brain; Cancer Biology; Caring; ChIP-seq; Chromatin Structure; Co-Immunoprecipitations; Cognitive deficits; Data; Dementia; Development; Early Intervention; Elderly; Environment; Epigenetic Process; Failure; Fellowship; Female; Foundations; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Goals; HDAC3 gene; Hippocampus; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Impaired cognition; Impairment; Individual; Intervention; Learning; Long-Term Potentiation; Measures; Memory; Memory impairment; Molecular; Molecular Neurobiology; Mus; Nerve Degeneration; Older Population; Phosphoric Monoester Hydrolases; Phosphorylation; Physiology; Population; Prevalence; Protein Dephosphorylation; Research; Research Personnel; Resources; Rodent Model; Role; Serine; Site; Slice; Synaptic plasticity; Testing; Therapeutic Intervention; Training; Transcription Process; Viral; Virus; Western Blotting; Wood material; age related; aged; aging brain; aging hippocampus; cancer cell; career; cognitive function; epigenetic regulation; experience; experimental study; healthy aging; histone acetyltransferase; human old age (65+); improved; long term memory; male; memory consolidation; mutant; neuropathology; novel; preservation; protein protein interaction; synaptic function; tool; transcriptome sequencing; upstream kinase; young adult

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.

项目概要/摘要 无法形成和存储长期记忆是衰老和神经退行性疾病中认知能力下降的一个特征。 专家预测，认知障碍（从轻度到重度痴呆）的患病率将会增加 随着美国 65 岁及以上老年人口的迅速增长，给 为老年人提供资源和护理。需要了解表观遗传和分子 老化大脑中的记忆形成机制，以制定早期干预策略并保存 老年认知功能。正如我们实验室和其他实验室所观察到的，组蛋白脱乙酰酶 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剂。然而，HDAC3 的调节机制 衰老的大脑在记忆方面仍然没有明确的定义。新数据表明 HDAC3 可能是 在癌细胞中受到上游激酶和磷酸酶的调节使我推测磷酸化 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，HDAC3 磷酸化机制在记忆过程中失调 衰老大脑中的巩固，导致与年龄相关的记忆障碍。本期初步数据 该提案表明，衰老小鼠（18 个月）海马体中磷酸化 HDAC3 的基线水平降低 与年轻成年小鼠（3个月）相比。此外，我开发了 HDAC3 突变病毒构建体来测试 磷酸化 HDAC3（磷酸模拟）和去磷酸化 HDAC3（磷酸无效）在记忆中的功能 年轻人和衰老大脑的形成和突触可塑性。初步结果表明，病毒 HDAC3 磷酸模拟物的表达会损害年轻成年小鼠的记忆形成和突触可塑性。 然而，衰老小鼠中 HDAC3 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 HDAC3 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，本提案将重点关注 继续研究 HDAC3 磷酸化对成人记忆形成的表观遗传调控 以及衰老的男性和女性大脑。本提案中的具体目标将确定以下内容： 目标 1，确定 HDAC3 磷酸化在年轻成人大脑中的作用；目标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 年轻成人和衰老大脑中的形成。该项目的发现可能会阐明一部小说 记忆中 HDAC3 表观遗传调控机制可能对所有衰老产生根本影响 有认知障碍的人。该培训奖学金将允许分子、 生理学和生物信息学专业知识。在伍德博士的指导下以及研究和专业人士的指导下 在 UCI 的环境中，该奖学金将为独立调查员的成功职业生涯奠定基础 专注于了解衰老大脑学习和记忆背后的表观遗传机制。