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.

项目摘要/摘要 未能形成和存储长期记忆是衰老和神经退行性变化的认知能力下降的特征。 专家预测，从轻度到重度痴呆症的认知障碍的患病率将增加 与65岁及65岁以上的美国老年人的迅速增长一起，为 为老年人提供资源和护理。有必要了解表观遗传和分子 衰老大脑中记忆形成的机制，以制定早期干预策略并保存 老年认知功能。正如我们在实验室和其他人中观察到的那样，组蛋白脱乙酰基酶3（HDAC3）是一个强大的 记忆形成和突触可塑性的表观遗传调节剂。但是，调节HDAC3的机制 关于记忆的衰老大脑仍然不确定。新兴数据表明HDAC3可能是 通过上游激酶和磷酸酶在癌细胞中调节，导致我假设磷酸化 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，在记忆中，HDAC3磷酸化的机制变得失调 衰老大脑的巩固，导致与年龄相关的记忆障碍。初步数据 提案表明，衰老小鼠的海马（18-MO）的基线水平降低了磷酸-HDAC3 与年轻的成年小鼠（3-MO）相比。此外，我开发了HDAC3突变病毒构建体以测试 记忆中磷酸化的HDAC3（磷酸化模拟）和去磷酸化的HDAC3（磷酸化）的功能 年轻人和衰老的大脑的形成和突触可塑性。初步结果表明病毒 HDAC3磷酸模拟的表达会损害年轻小鼠的记忆形成和突触可塑性。 但是，在老化小鼠中，HDAC3磷酸无效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，该提议将重点放在 继续研究成年人记忆形成的HDAC3磷酸化的表观遗传调节 和衰老的男性和女性大脑。该提案中的具体目的将确定以下确定：目标1，确定 HDAC3磷酸化在年轻大脑中的作用； AIM 2，确定HDAC3磷酸化的作用 在衰老的大脑中； AIM 3，确定HDAC3磷酸化调节记忆的机制 年轻人和大脑衰老的形成。该项目的发现可能会阐明新颖 在记忆中HDAC3表观遗传调节的机制，可能会对所有衰老产生基本影响 认知障碍的人。该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，研究和专业人士 UCI的环境，该奖学金将为成功的职业生涯奠定基础 专注于了解衰老大脑中学习和记忆的表观遗传机制。