Epigenetic regulation of the circadian gene Per1 in age-related memory impairments

昼夜节律基因 Per1 在年龄相关记忆障碍中的表观遗传调控

基本信息

批准号：
10171743
负责人：
JANINE LYNN KWAPIS
金额：
$ 24.9万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171743
关键词：
Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease American Animals CREBBP gene California Chromatin Structure Circadian Dysregulation Circadian Rhythms Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Data Deacetylase Development Development Plans Disease Dorsal Engineering Environment Epigenetic Process Foundations Functional disorder Funding Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Engineering Genetic Transcription Goals Grant HDAC3 gene Hippocampus (Brain)Histone Acetylation Impaired cognition Impairment Individual Institution Intervention Job Application Laboratories Lead Learning Link Mediating Memory Memory impairment Molecular Molecular Biology Mus Periodicity Play Population Positioning Attribute Process Regulation Repression Research Research Personnel Role Scientist Site Small Interfering RNA Technical Expertise Technology Testing Time Training Universities Virus Writing age related aging brain aging hippocampus base career chromatin immunoprecipitation chromatin remodeling circadian circadian pacemaker circadian regulation cognitive function design epigenetic regulation experience experimental study gene repression histone acetyltransferase histone modification juvenile animal knock-down long term memory memory consolidation mild cognitive impairment mutant neuromechanism normal aging novel novel therapeutics overexpression prevent programs promoter protein protein interaction remediation skills transcriptome sequencing treatment strategy

项目摘要

Project Summary/Abstract Alzheimer's Disease affects 5.4 million Americans [1] and by 2030, approximately 13.8 million people 65 or older are projected to have the disease [2]. Even more individuals will experience normal age-related cognitive decline, mild cognitive impairment, and impairments in long-term memory formation. It is therefore critical to understand the mechanisms underlying memory formation in the context of normal age-dependent cognitive decline. This proposal tests whether Per1 is a key novel mechanism that links aberrant epigenetic transcriptional repression in the aging brain with age-related impairments in both circadian rhythmicity and long-term memory formation. First, this proposal will test whether the repressive activity of histone deacetylase 3 (HDAC3) contributes to age-related impairments in both memory formation and gene expression. Next, it will determine whether Per1 is a mechanism through which HDAC3 limits memory formation in the aging brain. Finally, using a CRISPR/dCas9-based genetic engineering approach, this project will test whether site-specific epigenetic manipulations at Per1 can ameliorate age-related impairments in memory formation. Together, the experiments in this proposal will determine whether epigenetic dysregulation of the circadian gene Per1 in the dorsal hippocampus contributes to age-related impairments in long-term memory formation. The proposed project will also help the candidate, Dr. Janine Kwapis, achieve her career goal of becoming an independent investigator at a research-focused institution. This project provides training in cutting-edge research skills, including the development and application of CRISPR/dCas9 technology and training in circadian rhythm research. Further, the proposed studies will lay the foundation for a research program that extends well beyond the proposed grant. The University of California, Irvine provides an ideal environment for training the candidate in these new technical skills, with world-renowned experts in memory, aging, circadian rhythms, and molecular biology. Further, UCI provides an intellectual environment that encourages collaboration and cooperation, allowing the candidate to grow as a scientist and prepare for a successful career. In addition to the proposed research, Dr. Kwapis will engage in a number of activities designed to prepare her to successfully achieve independence, including training in grantsmanship, presentations, scientific writing, didactic training, job application, and lab management. The systematic plan proposed here (including both the research plan and the candidate development plan) is calibrated to produce a successful, independent research scientist who performs unique cutting-edge research that can support a new laboratory and is well-positioned to receive future R01 funding.

项目概要/摘要阿尔茨海默病影响着 540 万美国人 [1]，到 2030 年，大约有 1,380 万人 65 或老年人预计患有这种疾病[2]。更多的人将经历正常的与年龄相关的认知衰退、轻度认知障碍和长期记忆形成障碍。因此至关重要的是了解正常年龄依赖性认知背景下记忆形成的机制衰退。该提案测试了 Per1 是否是连接异常表观遗传的关键新机制衰老大脑中的转录抑制与年龄相关的昼夜节律和长期记忆的形成。首先，该提案将测试组蛋白脱乙酰酶的抑制活性是否 3 (HDAC3) 会导致记忆形成和基因表达方面与年龄相关的损伤。接下来，它将确定 Per1 是否是 HDAC3 限制衰老大脑中记忆形成的机制。最后，该项目将使用基于 CRISPR/dCas9 的基因工程方法来测试位点特异性是否 Per1 的表观遗传操作可以改善与年龄相关的记忆形成障碍。在一起，本提案中的实验将确定昼夜节律基因 Per1 的表观遗传失调是否存在于背侧海马体会导致与年龄相关的长期记忆形成障碍。拟议的项目还将帮助候选人 Janine Kwapis 博士实现她的职业目标，即成为以研究为重点的机构的独立调查员。该项目提供尖端培训研究技能，包括CRISPR/dCas9技术的开发和应用以及相关培训昼夜节律研究。此外，拟议的研究将为以下研究计划奠定基础：远远超出了拟议的赠款范围。加州大学欧文分校为学生提供了理想的环境与记忆、衰老、昼夜节律方面的世界知名专家一起对候选人进行这些新技术技能的培训节律和分子生物学。此外，UCI 还提供了一个鼓励协作与合作，让候选人成长为一名科学家，并为成功的成功做好准备职业。除了拟议的研究之外，Kwapis 博士还将参与一系列旨在帮助她做好成功独立的准备，包括资助、演讲、科学写作、教学培训、工作申请和实验室管理。这里提出的系统计划（包括研究计划和候选人发展计划）经过校准以产生成功的、独立研究科学家，进行独特的前沿研究，可以支持新实验室并有能力获得未来的 R01 资金。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A neuroscientist's guide to transgenic mice and other genetic tools.

转基因小鼠和其他遗传工具的神经科学家指南。

DOI：
发表时间：
2020-01
期刊：
影响因子：
8.2
作者：
Navabpour, Shaghayegh;Kwapis, Janine L;Jarome, Timothy J
通讯作者：
Jarome, Timothy J

Time to learn: The role of the molecular circadian clock in learning and memory.

学习时间：分子生物钟在学习和记忆中的作用。

DOI：
发表时间：
2022-09
期刊：
影响因子：
2.7
作者：
Smies, Chad W;Bodinayake, Kasuni K;Kwapis, Janine L
通讯作者：
Kwapis, Janine L

The clock gene Per1 is necessary in the retrosplenial cortex-but not in the suprachiasmatic nucleus-for incidental learning in young and aging male mice.

时钟基因 Per1 在压后皮层中是必需的，但在视交叉上核中不是必需的，对于年轻和老年雄性小鼠的偶然学习来说。

DOI：
发表时间：
2023-06
期刊：
影响因子：
4.2
作者：
Brunswick, Chad A;Baldwin, Derek J;Bodinayake, Kasuni K;McKenna, Alexandria R;Lo, Chen;Bellfy, Lauren;Urban, Mark W;Stuart, Emily M;Murakami, Shoko;Smies, Chad W;Kwapis, Janine L
通讯作者：
Kwapis, Janine L

The circadian clock gene Per1 modulates context fear memory formation within the retrosplenial cortex in a sex-specific manner.

生物钟基因 Per1 以性别特异性方式调节压后皮层内情境恐惧记忆的形成。

DOI：
发表时间：
2021
期刊：
影响因子：
2.7
作者：
Urban, Mark W;Lo, Chenyu;Bodinayake, Kasuni K;Brunswick, Chad A;Murakami, Shoko;Heimann, Ashley C;Kwapis, Janine L
通讯作者：
Kwapis, Janine L