In mammals, viral double-stranded RNA (dsRNA) triggers a response to pathogen by binding to host dsRNA binding proteins (dsRBPs). Increasingly, dsRBPs are also associated with diseased states, where a viral infection is not apparent, and the source of the dsRNA is unclear. The proposed research will explore the hypothesis that dsRNA transcribed from an animal's own genome is involved. In this model, an animal would have a characteristic pool of cellular dsRNA that would reflect metabolic state. Rapid and transient changes in dsRNA levels might occur during stress, or disease, while gradual changes during the lifetime of an animal would be part of the normal aging process. Studies to test the hypothesis will use the model organism C. elegans, as well as mammalian cells. Animals or cells will be engineered to overexpress dsRNA to test for a direct connection between levels of cellular dsRNA and the gene expression profiles and phenotypes associated with stress and aging. Sensitive high-throughput sequencing techniques will be used to identify the endogenous cellular dsRNA that serves to signal these processes. Identified cellular dsRNA and dsRBPs will be monitored for levels during stress or aging. Reagents for research and clinical purposes will be developed for the easy detection of dsRNA and to inhibit binding of dsRNAs to their target dsRBPs. The proposed experiments may uncover a previously unrecognized network of cellular dsRNA signaling molecules responsible for triggering pathways implicated in stress, autoimmunity and longevity, and set the stage for treatment and diagnosis of associated disease.
The proposed research may reveal that the causative agent in many diseased states is double-stranded RNA encoded by an animal's own genome. This knowledge would promote a huge shift in current paradigms and redirect research in ways that would accelerate progress in understanding disease and aging, and spur the search for diagnostic reagents to detect dsRNA, and therapeutic agents to inhibit its binding to proteins that elicit detrimental responses.
|Blango, Matthew G; Bass, Brenda L (2016) Identification of the long, edited dsRNAome of LPS-stimulated immune cells. Genome Res 26:852-62|
|Sinha, Niladri K; Trettin, Kyle D; Aruscavage, P Joseph et al. (2015) Drosophila dicer-2 cleavage is mediated by helicase- and dsRNA termini-dependent states that are modulated by Loquacious-PD. Mol Cell 58:406-17|
|Whipple, Joseph M; Youssef, Osama A; Aruscavage, P Joseph et al. (2015) Genome-wide profiling of the C. elegans dsRNAome. RNA 21:786-800|
|Youssef, Osama A; Safran, Sarah A; Nakamura, Takahisa et al. (2015) Potential role for snoRNAs in PKR activation during metabolic stress. Proc Natl Acad Sci U S A 112:5023-8|