Sunday, May 18, 2025
5/18/2025
Mitochondria-derived dsRNA in brain aging and Alzheimer's disease - PROJECT SUMMARY This F32 application is intended to support Dr. Rachel Doser’s postdoctoral research and training, and to effectively prepare her for a career as an independent researcher. Dr. Doser is a new (<6 months) postdoctoral research associate in Dr. Tom LaRocca’s Healthspan Biology Lab at Colorado State University. Under this fellowship, Dr. Doser will investigate a novel contribution of mitochondria-derived double-stranded RNA (mt-dsRNA) to neuroinflammation in aging and Alzheimer’s disease (AD). The rationale for the proposed studies is that dsRNA is a potent activator of innate immune/inflammatory signaling, and mitochondria are a major source of dsRNA, as bidirectional transcription of the circular mitochondrial genome results in the formation of mt-dsRNAs. Although mt-dsRNA-induced immune activation has been shown to contribute to certain cancers and autoimmunity, it has not been studied in the central nervous system, or in the context of aging or age-related neurodegenerative disease. However, mitochondrial dysfunction has been shown to correlate with increased mt-dsRNA formation, and dysfunctional mitochondria are a key hallmark of both aging and AD that may precede neuroinflammation, especially in metabolically demanding neurons. Thus, investigating the downstream effects of mitochondrial dysfunction in neurons due to aging and/or AD will advance our understanding of how aging increases the risk of AD and neurodegeneration in general. The preliminary data presented in this proposal suggest that mt-dsRNAs are released with older age and in AD, and that they correlate with increased expression of dsRNA immune sensors. Therefore, the proposed research is designed to test the hypothesis that age/AD-related mitochondrial dysfunction leads to release of mt-dsRNAs that instigate an innate immune response. First (Aim 1), Dr. Doser will use both in vitro and in vivo organismal models to determine if age/AD-related mitochondrial dysfunction contributes to mt- dsRNA release. Then (Aim 2), she will use similar approaches to determine if mt-dsRNAs cause neuroinflammation. Finally (Aim 3), Dr. Doser will investigate if /how mt-dsRNA levels correlate with cognitive function or AD pathology in humans. Together, these aims will detail the hypothesized mechanism linking age/AD-related mitochondrial dysfunction to neuroinflammation and assess its relevance to human health/function, and they may identify novel targets for preventing or limiting inflammation. The proposed studies will provide Dr. Doser with extensive new training in translational research using multiple models. She will leverage and expand her current skillset, including by learning new cutting-edge techniques such as bioinformatics, human neuronal cell culture and reprogramming, measurements of mitochondrial function and clinical/data science. The relevant expertise of Dr. Doser’s sponsor, Dr. LaRocca, and consulting mentors Drs. Karyn Hamilton and Chris Link, will support successful completion of the proposed aims and provide Dr. Doser with an exceptional, interdisciplinary and translational research training experience.
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