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

项目摘要 此NIH F32培训应用程序的目的是为迪文瓦尔博士的研究提供支持， 培训，这将使他准备成为一个独立的调查研究大脑老化，年龄相关 认知功能障碍和阿尔茨海默病（AD）。瓦尔博士是博士的第一年博士后研究员。 托马斯拉罗卡在科罗拉多州立大学的实验室。他之前有临床前啮齿动物研究的经验， 大脑老化，但根据这项训练计划，他将学习拉罗卡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，发展临床前AD研究的专业知识（一个新的 场为他）。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， 研究和专业独立性。在这个项目中，Wahl博士将研究重复的作用， 元件（RE）转录物（来自基因组中的非编码重复序列）在脑老化中的作用， AD. RE在关于衰老的生物医学研究中通常被忽视，但我们发表的/初步的数据和 来自其他研究小组的报告表明，衰老与RE转录本的积累有关， 这些转录物可以调节几个主要的“衰老标志”，如炎症。尚不清楚 RE转录本的积累是否在大脑衰老（以及与年龄相关的AD）中起作用，但Dr。 Wahl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 和神经炎症表明这很可能是事实。因此，在本项目的目标1中，Wahl博士将学习 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RE表达的大脑老化，他将探索现有的人类数据集 受试者以确定RE是否与脑老化/AD相关。在目标2中，他将联合收割机与他的 既往进行临床前药理学干预研究的经验（使用已确立的RE 抑制剂）以确定抑制RE是否抑制神经炎症和脑老化/AD。的结果 培训补助金可以解决NIA的几个重要研究优先事项，包括确定新的 脑老化/AD的分子调节剂和改善脑健康的潜在治疗靶点， 预防与年龄相关的AD。赞助商LaRocca博士是由美国国立卫生研究院资助的，用于研究衰老和AD中的RE转录本。 在这方面有着成功的历史。他将指导Wahl博士进行这项研究的各个方面。 Wahl还将接受包括Seals博士、Hoeffer博士、Moreno博士在内的技术/专业专家团队的指导， 汉密尔顿和林克谁将提供对瓦尔博士的研究和职业生涯的其他方面的指导。瓦尔医生 在研究衰老/大脑衰老方面已经有了很好的记录。因此，有了这个专家导师团队 他将能够成功地完成概述的调查，并沿着发展新的技能 新的调查路线将加速他成为一名成功的独立调查员的道路。

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.