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

项目摘要/摘要 阿尔茨海默病影响着540万美国人[1]，到2030年，大约有1380万人65岁或以上 老年人预计会患上这种疾病[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 在正常年龄依赖的认知背景下理解记忆形成的潜在机制 拒绝。这项提议测试了PER1是否是将异常的表观遗传联系起来的关键的新机制 具有昼夜节律性和年龄相关性损害的老化脑中转录抑制 长期记忆的形成。首先，这项提议将测试组蛋白脱乙酰酶的抑制活性 3(HDAC3)导致与年龄相关的记忆形成和基因表达障碍。接下来，它将 确定PER1是否是HDAC3限制老化大脑中记忆形成的机制。 最后，使用基于CRISPR/dCas9的基因工程方法，该项目将测试特定部位 PER1的表观遗传操作可以改善记忆形成中与年龄相关的损伤。团结在一起， 这项提议中的实验将确定昼夜节律基因PER1的表观遗传失调是否在 在长期记忆形成中，背侧海马区与年龄相关的损害有关。 拟议的项目还将帮助候选人Janine Kuapis博士实现她的职业目标，成为 一家专注于研究的机构的独立调查员。该项目提供尖端技术方面的培训 研究技能，包括CRISPR/dCas9技术的开发和应用以及 昼夜节律研究。此外，拟议的研究将为一项研究计划奠定基础 远远超出了拟议的拨款范围。加州大学欧文分校为 与世界知名的记忆、衰老、昼夜节律方面的专家一起培训候选人这些新的技术技能 节律和分子生物学。此外，UCI提供了一个智力环境，鼓励 协作与合作，使候选人能够成长为一名科学家，并为成功的 职业生涯。除了拟议的研究外，夸皮斯博士还将参与一系列旨在 为她成功地实现独立做好准备，包括培训勇气、演讲、 科学写作、教学培训、求职申请和实验室管理。在这里提出的系统计划 (包括研究计划和候选人发展计划)被校准以产生一个成功的、 执行可支持新实验室的独特尖端研究的独立研究科学家 并处于有利地位，可以获得未来的R01资金。

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.