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

重复元件转录在大脑衰老和阿尔茨海默病中的作用

• 批准号: 10471184
• 负责人: Devin Wahl
• 金额: $ 6.98万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471184
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid beta-Protein; Area; Biochemical Markers; Bioinformatics; Biomedical Research; Brain; Caloric Restriction; Career Choice; Chronic Disease; Clinical Pharmacology; Code; Cognitive aging; Colorado; Complement; Data; Data Reporting; Data Set; Funding; Gene Expression; Genes; Genome; Grant; Human; Immune; Impaired cognition; Inflammation; Intervention; Intervention Studies; Investigation; Laboratories; Learning; Link; Mentors; Molecular; Mus; Neurodegenerative Disorders; Pathology; Peripheral; Pharmacological Treatment; Pharmacology; Play; Poly A; Postdoctoral Fellow; Proteins; Publishing; RNA; RNA Computations; Recording of previous events; Repetitive Sequence; Reporting; Research; Research Personnel; Research Priority; Research Training; Reverse Transcriptase Inhibitors; Risk Factors; Rodent; Role; Sampling; Senile Plaques; Techniques; Testing; Training; Transcript; Transgenic Organisms; United States National Institutes of Health; Universities; Untranslated RNA; Use of New Techniques; Wild Type Mouse; Work; age related; age related neurodegeneration; aging brain; anti aging; base; brain health; career; cognitive function; effective intervention; experience; human subject; improved; inhibitor; insight; mild cognitive impairment; mouse model; neglect; neuroinflammation; novel; pre-clinical; prevent; seal; sensor; skills; spatial memory; success; tau aggregation; therapeutic target; transcriptome; transcriptome sequencing; transgenic model of alzheimer disease

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.

项目摘要 F32培训申请的目的是为Devin Wahl博士的研究提供支持，并 培训将使他成为研究大脑衰老的独立研究人员，与年龄相关 认知功能障碍和阿尔茨海默氏病（AD）。 科罗拉多州立大学的托马斯·拉罗卡（Thomas Larocca）实验室。 大脑衰老，但根据培训计​​划，他将在Larocca中学习各种新技术 实验室（例如，生物信息学）并与联合学者合作开发临床前广告研究的专业知识（一种新的 对他来说，这项工作将补充Wahl博士的现有专业知识，并使他处于职业生涯中 研究和专业独立性。 元素（re）转录本（源自基因组中的非编码重复序列），脑衰老和 广告中，通常在衰老的生物医学研究中忽略了 其他小组的报告表明，衰老与 这些transtt可能会调节几个主要的“衰老的标志” 重新转录本是否在大脑衰老中起作用 Wahl的强大初步数据和最新报告是与年龄有关的神经退行性疾病 因此，神经炎症可能是这样的。 并使用先进的生物信息学方法（例如RNA-Seq）探索各种干预措施的影响 已知以模块化大脑在小鼠的重新表达中的模块化衰老，他将在人类上探测现有的数据集 受试者确定是否与AIM 2中的大脑衰老/AD联系在一起 进行临床前药理学干预研究的先前经验（使用已建立的RE 抑制剂）确定抑制RE是否抑制神经炎症和大脑敏捷/AD。 培训赠款可以解决NIA的严重研究重点，包括识别新颖 大脑衰老/AD潜在疗法的分子调节剂，以改善大脑健康和 预防与年龄相关的AD。 并在这一领域有成功的历史。 Wahl还将由海豹突击队，Hoeffer，Moreno，Moreno，Moreno的技术/专业专家团队进行指导。 汉密尔顿和林克将提供Wahl博士研究和职业的其他方面。 这项专家导师团队已经在衰老/大脑衰老方面具有很强的记录。 他将能够为概述的调查和发展提供新技能。 新颖的调查系列将使他走上成为成功的独立研究者的道路。