What we study
The role of transfer RNAs in acute respiratory distress syndrome
tRNAs are increasingly acknowledged as essential regulators in various human diseases. However, their role in critical illness has yet to be explored.
Classically considered passive mRNA translators, tRNA expression is dynamic with tissue- and cell-specificity. Multiple cellular stressors alter the abundance and modification of individual tRNAs. Post-transcriptional modification of tRNAs, primarily by methylation, regulates tRNA stability and may prevent tRNA fragmentation. Stress-induced tRNA-derived fragments are a major source of small non-coding RNAs. Like microRNAs, tRNA-derived fragments are biologically active, impacting many cellular processes, and are abundant biomarkers in biologic fluids. Despite this, the role of tRNAs, tRNA fragments, and their regulation in infection and critical illness is unknown.
Molecular profiling of individuals with critical illnesses
We utilize our extensive ICU biorepository, which includes longitudinal samples from critically ill patients, to elucidate disease mechanisms and discover new targets for further research.
The Ohio State University ICU Registry and Prospective Cohort Study (BuckICU). To support translational research investigating critical illness, we developed BuckICU, a collaborative biorepository effort among investigators at OSU. I serve as the principal investigator (PI) of BuckICU. This single center, prospective cohort study collects clinical data and biological samples from adult hospitalized patients with acute respiratory failure, suspicion of sepsis, or both. We collect 1) blood specimens on days 1, 3, 7, 10 and 21; 2) endotracheal aspirate (ETAs) at days 1 and 7; 3) excess ETAs or bronchoalveolar lavage fluid (as clinically indicated); 4) an oral swab for host genomics and microbiome studies; and 5) excess urine on days 1, 3, 7, 10 and 21. Clinical and laboratory data are collected throughout the study period. Clinical measures include: Patient medical history, (including pre-existing conditions, smoking/vaping, exposures), sequential chest imaging (CT scans and CXR), Sequential Organ Failure Assessment score, PaO2/FiO2 ratio, ventilator/oxygen supplementation, daily vitals (median and range), clinical laboratory investigations (blood counts, electrolyte panel, ferritin, CRP, IL-6), and outcomes measures (ventilator-free days, survival). To date, we have enrolled over 280 subjects with over 12,500 unique biologic samples banked.
Protein degradation in ARDS and sepsis
Ubiquitination is a universal molecular modification that tags proteins for degradation and governs vital cellular processes, such as cell death and responses to environmental stimuli.
Ubiquitin (Ub) is a ~8kDa protein, covalently attached to a lysine residue of a substrate protein to direct protein cellular trafficking. Ubiquitin molecules are added to lysine residues of a substrate protein individually (mono-ubiquitination) or as a chain (poly-ubiquitination). The characteristics of this chain determine how the substrate protein is trafficked. Ubiquitin chains linked at the lysine-48 residue (Lys48 or K48) are the most abundant linkage type observed in cells, and K48 ubiquitin modification traffics substrates to the proteasome for degradation. Comprehensive proteomics studies suggest that most proteins will experience ubiquitination, each modified by multiple ubiquitin chains, during their cellular lifetime. Ubiquitination is affected by the dynamic balance of ubiquitin ligases (E3 ligases) and deubiquitinases (DUBs). The dynamic balance between E3 ligases and DUBs alter the abundance and subcellular location of cellular proteins to impact vital cellular process such as cell cycle, apoptosis, and response to external stimuli. Our group has demonstrated the role of DUBs in regulation of innate immunity during ARDS.