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

项目总结/摘要 阿尔茨海默病影响540万美国人[1]，到2030年，大约有1380万65岁或 老年人患上这种疾病[2]。甚至更多的人会经历正常的与年龄相关的认知障碍。 衰退、轻度认知障碍和长期记忆形成障碍。因此， 理解在正常的年龄依赖性认知背景下记忆形成的机制 下降这项提案测试Per 1是否是一个关键的新机制，连接异常的表观遗传 转录抑制在老龄化的大脑与年龄相关的损害，在这两个昼夜节律和 长期记忆的形成首先，这项建议将测试组蛋白去乙酰化酶的抑制活性是否 3（HDAC 3）有助于记忆形成和基因表达的年龄相关损伤。接下来将 确定Per 1是否是HDAC 3限制衰老大脑中记忆形成的机制。 最后，使用基于CRISPR/dCas 9的基因工程方法，该项目将测试是否具有位点特异性。 Per 1的表观遗传操作可以改善记忆形成中与年龄相关的损伤。统称 这项建议中的实验将确定是否在昼夜节律基因Per 1的表观遗传失调， 背侧海马有助于长期记忆形成中的年龄相关损伤。 拟议的项目也将帮助候选人，博士珍妮Kwapis，实现她的职业目标，成为 一个研究机构的独立调查员该项目提供尖端技术培训， 研究技能，包括CRISPR/dCas 9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， 远远超出了拟议的补助金。加州大学欧文分校为学生提供了理想的学习环境。 培训候选人在这些新的技术技能，与世界知名的专家在记忆，老化，昼夜节律 节奏和分子生物学。此外，UCI还提供了一个知识环境，鼓励 协作与合作，让候选人成长为一个科学家，并为成功的 事业除了拟议的研究外，Kwapis博士还将从事一些活动， 准备她成功地实现独立，包括培训granitarian，介绍， 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）进行校准，以产生一个成功的， 独立研究科学家，进行独特的尖端研究，可以支持新的实验室 并准备好接受未来的R 01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.