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

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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.