Research topics
Overview
Our lab's main research interest lies in the emerging interdisciplinary biomedical research on noncoding RNAs. In particular, we are interested in studying the pathophysiological role of double-stranded RNAs (dsRNAs) that can activate the innate immune response systems. We identify endogenously expressed dsRNAs using high-throughput sequencing and investigates their biological function through interaction with dsRNA-binding proteins via systems-level analysis. By studying dsRNAs, we provide a new direction in understanding the pathogenesis of various human diseases, including but not limited to osteoarthritis and autoimmune diseases where aberrant immune activation is observed. By doing so, we establish RNA-based diagnostic markers and suggest potential therapeutic targets in fighting the disease.
Aberrant immune activation by endogenous double-stranded RNAs
Historically, double-stranded RNAs (dsRNAs) were believed to be byproducts of viral replication and a signature molecule of viral infection. As the first-line defense against foreign materials, innate immune response proteins such as Protein-kinase R (PKR) and Melanoma differentiation-associated gene 5 (MDA5) are evolved to recognize these features and induce the downstream interferon response and initiate the apoptotic programs.
Recently, increasing evidence suggests that human cells naturally express cellular dsRNAs that can regulate antiviral machinery in a controlled manner. Considering that aberrant activation of PKR and other immune response proteins is implicated in numerous human diseases, we believe that cellular dsRNAs may have a key role in the onset and progression of the diseases, particularly inflammatory and degenerative diseases that accompany aberrant immune activation. Therefore, we aim to identify novel cellular dsRNAs and study their function to better understand how they are associated with human diseases that accompany aberrant immune activation.
Image credit: Kim Y et al. Mol Cell, 2018.
Pathological function of double-stranded RNAs
A critical aspect of the current dsRNA research is the strong biomedical implication of dsRNAs and their interacting partners. For example, during wound healing, dsRNAs (yet unknown identity) are released to the extracellular space and work as a means of cell-to-cell communication. In addition, the accumulation of dsRNAs is reported to be the cause of age-related macular degeneration. In fact, activation of PKR is commonly observed in neurodegenerative diseases, but its activating cue remains largely unknown.
Motivated by these studies, we are actively investigating the role of cellular dsRNAs in the onset of human diseases where aberrant activation of immune response proteins is implicated.
Double-stranded RNAs in cancer treatment
The expression of dsRNAs are usually silenced in cells as these RNAs can activate innate immune response. By reactivating their expression, we can trigger innate immune response in cancer cells which subsequently result in immunogenic cell death. Our lab is interested in utilzing the immunogenic potential of dsRNAs in cancer treatment
RNA engineering for mRNA vaccine
One key challenge in developing effective mRNA vaccine is controlling innate immune activation by in vitro transcribed mRNAs. During in vitro transcription, double-stranded RNAs are generated as byproducts and when introduced to cell, these RNAs activate innate immune response systems which result in decreased translation and increased cytotoxicity. Our lab is actively working on engineering mRNA structures in order to control innate immune activation by in vitro transcribed mRNAs
Double-stranded RNA sensors for theranostics
Double-stranded RNAs are signature of viral infection and numerous human diseases are traced back to aberrant expression of cellular dsRNAs. Our lab is interested in developing small molecules for dsRNA detection and treatment. Spiropyrans are photochromic dyes which have binding properties to nucleic acids.
Interestingly, interacting of spiropyran and nucleic acids results in shifts in light absorbance spectra. Furthermore, due to their photo-switching properties, they are often used to modulate processes with light. We have used spiropyran to sense and detect dsRNAs from cellular samples and applied spiropyran as a tool for predicting the efficacy of anticancer drugs that induce dsRNAs as a mean to kill cancer cells.
Image credit: Kang M et al., Mol Ther Nuc Acids, 2022
Underlying mechanism of drug-resistance
Going beyond the cellular dsRNAs, we also engage in the study of the molecular mechanism behind the acquisition of drug resistance in cancer. Drug-resistant tumors allow cancer to recur or metastasize. Despite its inevitability, resistance is currently managed in the clinic through a rational sequence and cocktail of therapies. We used a combination of high-throughput data analysis, computational modeling, and molecular biology approach to understand the changes that occur during the acquisition of drug resistance to develop effective therapeutic strategies.
Through our investigation, we found the collateral resistance phenomenon where cancer cells acquiring resistance to anti-mitotic drugs also exhibited cross-resistance to a class of targeted therapies. We are currently investigating the utilization of dsRNA-mediated immune response as a strategy to overcome drug resistance.
Image credit: Aldonza MB et al., Sci Adv, 2020
