Saturday, May 4, 2024
5/4/2024
ABSTRACT This application, “Transfer RNAs as novel mediators in acute lung injury,” is submitted by Joseph S. Bednash, MD for a K08 Mentored Clinical Scientist Research Career Development Award. I am a physician-scientist in the Division of Pulmonary, Critical Care and Sleep Medicine at the Ohio State University (OSU). I am applying for this award for advanced training as a physician-scientist, studying mechanisms that contribute to dysregulated biology in ARDS and critical illness. The primary objective of my research plan is to determine how transfer RNA (tRNA)-derived fragments regulate host defense mechanisms in lung injury and to determine how TRMT1 (tRNA (guanine(26)-N(2))-dimethyltransferase), a tRNA methyltransferase and putative upstream regulator, modulates tRNA fragments to impact host defense. With cellular stress, tRNAs are fragmented into biologically active small non-coding RNAs, termed tiRNAs (tRNA halves) or tRFs (tRNA-derived fragments). TRMT1 methylates tRNAs, prevents tRNA fragmentation, and preserves protein translation efficiency. tRNAs, tRNA-derived fragments, and their control by TRMT1 has not been explored in ARDS and other critical illness syndromes. I present preliminary data demonstrating upregulation of tRNA fragments with bacterial endotoxin that promote cell death in macrophages. Further, I show that TRMT1 prevents tRNA fragments and preserves host defense mechanisms. The specific aims of this study are: 1) Determine how tRNA fragments contribute to immunopathology in ARDS and experimental lung injury, and 2) Define mechanisms whereby TRMT1 preserves inflammasome function in experimental lung injury. These studies will provide mechanistic insight into the role of tRNA fragments and their control by TRMT1 in lung injury and may identify novel strategies to augment host defense in ARDS. To accomplish these studies, I propose a training plan to acquire training in RNA molecular and cellular biology, training in microbial pathogenesis and immunology, and translational bioinformatics. To ensure success of my training and research plans, we have assembled a committed mentorship team, including i) Dr. Rama Mallampalli, Professor and Chair of Medicine at OSU, ii) Dr. Joshua Englert, an outstanding translational physician-scientist studying ARDS, iii) Dr. Federica Accornero, an expert in RNA modification in cardiac disease, and iv) Dr. Guy Brock, a biostatistician with expertise in translational bioinformatics. We have assembled a Scientific Advisory Committee to lend expertise, provide oversight, and evaluate progress, including i) Dr. Mallampalli, ii) Dr. Anuradha Ray, an expert in lung immunology, and iii) Dr. Ana Mora, an expert in mechanisms of lung injury and fibrosis. My work will be completed in the Division of Pulmonary, Critical Care, and Sleep Medicine at OSU, an excellent environment for my career development. With the guidance of mentors, the research environment at OSU, and support from the K08 Career Development Award, I am confident I can build my skillset and research program to support transition to independent R01 funding in the next five years.
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