The role of HDAC3 in age-related impairments in memory updating

HDAC3 在与年龄相关的记忆更新损伤中的作用

基本信息

批准号：
10039300
负责人：
JANINE LYNN KWAPIS
金额：
$ 42.97万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10039300
关键词：
Acetylation Address Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease American Brain CRISPR interference ChIP-seq Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats Cognition Data Diagnosis Disease Dorsal Enzymes Epigenetic Process Event Excision Future Gene Expression Genes Genetic Transcription HDAC3 gene Hippocampus (Brain)Histone Acetylation Histone Deacetylase Histone H4 Impaired cognition Impairment Individual Learning Location Lysine Memory Memory Loss Memory impairment Molecular Mus Pharmacology Population Process Records Repression Rodent Role Simplexvirus Techniques Testing Therapeutic Intervention Time Update Viral Work age related aging brain base chromatin immunoprecipitation cognitive function experience flexibility genome-wide human old age (65+)improved knock-down long term memory memory consolidation middle age mild cognitive impairment new therapeutic target next generation sequencing normal aging novel prevent response selective expression spatial memory stem targeted treatment transcriptome sequencing treatment strategy

项目摘要

Project Summary/Abstract: Alzheimer’s disease currently affects 5.8 million Americans and 13.8 million people over the age of 65 are expected to develop the disease by 2030. Even more individuals will experience normal age-related cognitive decline, including mild cognitive impairments and memory deficits. Understanding the molecular mechanisms that underlie these impairments is a key step toward developing treatments to prevent or reverse memory decline in both normal aging and Alzheimer’s disease. One hallmark of age-related cognitive decline is an impairment in memory updating, the ability to modify existing memories with new information. Memories do not persist in a fixed, unalterable state, but instead must be capable of being updated in response to new, relevant experiences. Indeed, most memories are updates to existing memories, rather than brand new associations. Despite its fundamental importance, little is known about the mechanisms that support memory updating and even less is understood about how these mechanisms are altered with age. To address this, we have developed a novel paradigm called the Objects in Updated Locations (OUL) task that is ideal for studying memory updating in both young and old rodents. In this proposal, we will examine the role of a key epigenetic mechanism, histone deacetylase 3 (HDAC3), in regulating gene expression during memory updating in the young and old brain. HDAC3 is a powerful enzyme that promotes a repressive chromatin structure to limit gene expression. Deletion or disruption of HDAC3 in the young brain transforms a subthreshold learning event into one that produces robust memory. Further, deleting HDAC3 in the dorsal hippocampus of old mice ameliorates age-related impairments in spatial memory formation. To date, no studies have tested the role of HDAC3 in memory updating or age- related impairments in memory updating. Here, we hypothesize that aberrant HDAC3 function in the old brain contributes to a repressive chromatin structure that disrupts the gene expression necessary for memory updating. In support of this hypothesis, our preliminary data show that pharmacological HDAC3 inhibition can ameliorate age-related memory updating impairments. To fully test this hypothesis, we propose two aims. In Aim 1, we will test the role of HDAC3 in age-related impairments in memory updating using a combination of pharmacological and viral CRISPR-based inhibition of HDAC3 selectively during a memory update. In Aim 2, we will use next generation sequencing including chromatin immunoprecipitation (ChIP) sequencing and RNA sequencing to identify the molecular mechanisms that underlie memory updating and determine how HDAC3 contributes to age-related impairments in this process. Our results will elucidate the mechanisms that support memory updating and identify HDAC3 as a critical regulator of memory updating in the young and old brain. These results represent a significant conceptual advance in our understanding of age-related memory decline and may identify potential targets for therapeutic intervention to improve cognition in old age.

项目摘要/摘要：目前，阿尔茨海默病影响着 580 万美国人，其中 1380 万 65 岁以上的人患有阿尔茨海默病。预计到 2030 年将患上这种疾病。更多的人将经历正常的与年龄相关的认知衰退，包括轻度认知障碍和记忆缺陷了解分子机制。这些损伤背后的原因是开发预防或逆转记忆衰退的治疗方法的关键一步在正常衰老和阿尔茨海默氏病中，与年龄相关的认知能力下降的一个标志是损害。在记忆更新中，用新信息修改现有记忆的能力不会持续存在。固定的、不可改变的状态，但必须能够根据新的相关经验进行更新。事实上，大多数记忆都是对现有记忆的更新，而不是全新的联想。至关重要的是，人们对支持内存更新的机制知之甚少，甚至更少为了了解这些机制如何随着年龄的增长而改变，我们开发了一本小说。称为“更新位置中的对象”(OUL) 任务的范例，非常适合研究两者中的内存更新在这项提议中，我们将研究关键的表观遗传机制——组蛋白的作用。脱乙酰酶 3 (HDAC3)，在年轻和年老大脑的记忆更新过程中调节基因表达。 HDAC3 是一种强大的酶，可促进抑制性染色质结构以限制基因表达。或破坏年轻大脑中的 HDAC3 会将阈下学习事件转变为产生强大的学习事件此外，删除老年小鼠背侧海马中的 HDAC3 可改善与年龄相关的损伤。迄今为止，还没有研究测试 HDAC3 在记忆更新或年龄相关中的作用。在这里，我们与旧大脑中异常的 HDAC3 功能作斗争。有助于抑制染色质结构，破坏记忆所需的基因表达为了支持这一假设，我们的初步数据表明药理学 HDAC3 抑制可以为了充分检验这一假设，我们提出了两个目标。 1，我们将使用以下组合来测试 HDAC3 在年龄相关损伤中更新记忆的作用：在记忆更新过程中，基于药物和病毒的 CRISPR 选择性抑制 HDAC3。将使用下一代测序，包括染色质免疫沉淀 (ChIP) 测序和 RNA 测序以确定记忆更新的分子机制并确定 HDAC3 在此过程中导致与年龄相关的损伤。我们的结果将阐明支持的机制。记忆更新并确定 HDAC3 是年轻和年老大脑中记忆更新的关键调节因子。这些结果代表了我们对与年龄相关的记忆衰退的理解的重大概念进步并可能确定治疗干预的潜在目标，以改善老年人的认知能力。