Role of repetitive element transcripts in brain aging and Alzheimer's disease

项目总结 此NIH F32培训应用程序的目的是为Devin Wahl博士的研究和 培训，这将使他成为一名研究大脑老化的独立调查者，与年龄相关 认知功能障碍与阿尔茨海默病(AD)瓦尔博士是博士后第一年研究员。 托马斯·拉罗卡在科罗拉多州立大学的实验室。他在啮齿动物的临床前研究方面有经验。 大脑老化，但在这个训练计划下，他将学习在LaRocca常规使用的各种新技术 实验室(例如，生物信息学)，并与共同导师合作，开发临床前AD研究的专业知识(新的 他的场地)。这项工作将补充Wahl博士现有的专业知识，并使他走上职业道路 研究和专业独立。在这个项目中，Wahl博士将研究重复的 元素(RE)转录本(源自基因组中的非编码重复序列)与大脑老化和 广告。Re在关于衰老的生物医学研究中通常被忽视，但我们公布的/初步数据和 来自其他小组的报告表明，衰老与RE转录的积累有关，而且 这些转录本可能调节几个主要的“衰老特征”，如炎症。这是未知的 RE转录积累是否在大脑老化(以及随后与年龄相关的AD)中发挥作用，但Dr。 Wahl的强有力的初步数据和最近的报告表明RE与年龄相关的神经退行性疾病有关 神经炎症表明情况很可能就是这样。因此，在这个项目的目标1中，Wahl博士将了解到 并使用先进的生物信息学方法(例如，RNA-seq)来探索各种干预措施的效果 已知调节小鼠大脑老化对RE表达的影响，他将探索现有的关于人类的数据集 受试者确定RE是否与脑老化/AD有关。在《目标2》中，他将把这些新技能与他的 有进行临床前药物干预研究的经验(使用已建立的RE 抑制剂)，以确定抑制RE是否抑制神经炎症和脑老化/AD。这样做的结果 培训补助金可能涉及国家投资局的几个重要研究优先事项，包括确定新的 脑老化/阿尔茨海默病的分子调节剂及其改善脑健康和治疗阿尔茨海默病的潜在靶点 预防老年性AD。赞助商LaRocca博士是由NIA资助的，用于研究衰老和AD的RE转录 在这一领域有着成功的历史。他将指导瓦尔博士这项拟议研究的方方面面。 Wahl还将得到一个技术/专业专家团队的指导，其中包括Seals博士、Hoeffer博士、Moreno博士、 汉密尔顿和林克博士将就瓦尔博士的研究和职业生涯的其他方面提供指导。瓦尔博士 在衰老/脑老化的研究方面已经有了很好的记录。因此，有了这支专家导师团队 他将能够成功地完成概述的调查，并随之而来发展新的技能 新颖的调查路线将加速他成为一名成功的、独立的调查员。

PROJECT SUMMARY The purpose of this NIH F32 training application is to provide support for Dr. Devin Wahl’s research and training that will prepare him to become an independent investigator studying brain aging, age-associated cognitive dysfunction and Alzheimer’s disease (AD). Dr. Wahl is a first-year postdoctoral fellow in Dr. Thomas LaRocca’s lab at Colorado State University. He has prior experience in pre-clinical rodent studies of brain aging, but under this training plan, he will learn a variety of new techniques used routinely in the LaRocca lab (e.g., bioinformatics) and work with co-mentors to develop expertise in pre-clinical AD studies (a new field for him). This work will complement Dr. Wahl’s existing expertise and put him on a career path towards research and professional independence. In this project, Dr. Wahl will investigate the role of repetitive element (RE) transcripts (derived from non-coding repetitive sequences in the genome) in brain aging and AD. RE are commonly overlooked in biomedical research on aging, but our published/preliminary data and reports from other groups indicate that aging is associated with an accumulation of RE transcripts, and that these transcripts may modulate several main ‘hallmarks of aging’, such as inflammation. It is unknown whether RE transcript accumulation plays a role in brain aging (and consequently age-related AD), but Dr. Wahl’s strong preliminary data and recent reports implicating RE in age-related neurodegenerative diseases and neuroinflammation suggest this is likely the case. Therefore, in Aim 1 of this project, Dr. Wahl will learn and use advanced bioinformatics approaches (e.g., RNA-seq) to explore the effects of various interventions known to modulate brain aging on RE expression in mice, and he will probe existing datasets on human subjects to determine if RE are linked with brain aging/AD. In Aim 2, he will combine these new skills with his prior experience to conduct a pre-clinical pharmacological intervention study (using an established RE inhibitor) to determine if suppressing RE inhibits neuroinflammation and brain aging/AD. The results of this training grant may address several important research priorities at NIA, including the identification of novel molecular modulators of brain aging/AD and potential therapeutic targets for improving brain health and preventing age-related AD. The sponsor, Dr. LaRocca, is NIA-funded to study RE transcripts in aging and AD and has a history of success in this area. He will guide Dr. Wahl on all aspects of the proposed study, and Dr. Wahl will also be mentored by a team of technical/professional experts including Drs. Seals, Hoeffer, Moreno, Hamilton and Link who will provide guidance on other aspects of Dr. Wahl’s research and career. Dr. Wahl already has a strong track record in research on aging/brain aging. As such, with this team of expert mentors he will be able to successfully complete the investigations outlined, and developing new skills along with this novel line of investigation will accelerate him on the path to becoming a successful, independent investigator.