The Platelet Transcriptome and Organ Failure After Injury: Discovering Molecular Biomarkers and Preventative Targets through Interrogating Novel RNA Modifications

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Project Summary/Abstract As a trauma surgeon-scientist and early stage investigator in the 5th year of an NIGMS mentored career development award for the translational study of post-injury platelet function, I have developed expertise, infrastructure, and made significant contributions to demonstrating that early platelet dysfunction after injury is common, driven by changing physiology, and associated with later development of organ failure. This is important because injury remains a leading cause of death worldwide, but advances in initial care have shifted the burden of injury-related morbidity and mortality from early after injury to later, leaving two important challenges:1) identifying injured survivors at highest risk of developing initial and sustained organ failure leading to long-term morbidity and late mortality, and 2) discovering novel targets for early therapies to prevent development of organ failure after injury. Platelets contribute to organ failure through pathobiology in thromboinflammation. In similar diseases, platelet transcriptomics has improved mechanistic understandings and driven exploration of platelet-based therapeutics. Platelet megakaryocyte derived ribonucleic acids (RNAs) are stable in health, but modified by physiological signals in disease. Importantly, platelets are anucleate and lack RNA synthesis, thus providing the cleanest transcriptomic view of RNA modification in human biology. As such, my proposal seeks to re- imagine how we understand, measure, and intervene on early alterations in platelets after injury by focusing on the platelet transcriptome to explore prediction and prevention of organ failure among patients who initially survive their injuries, and to identify RNA modification targets that can be tested in model systems by addressing these knowledge gaps: 1) Identify the early platelet transcriptional landscape of severe injury and its relationship to development and resolution of organ failure in longitudinal patient studies; 2) Define the effect of platelet RNA modifications on platelet function in samples from patients with severe injury and in ex vivo modified healthy platelets; 3) Develop ex vivo and in vitro model systems to manipulate clinically relevant platelet RNA modifications as ultimate conduits to in vivo models and clinical testing. I will use feasible (next generation sequencing, ribosome footprint profiling), and novel (sub-population sequencing, ex vivo transgenic platelet model systems) methods to identify novel molecular biomarkers and preventative targets of development of organ failure after injury, and innovate our understanding of physiologically driven RNA modification through the ideal anucleate biology of platelets under the optimal acute physiologic changes of injury. This K to R award transition proposal is NIGMS mission-focused by using basic research to increase understanding of biological processes and lay the foundation for advances in disease diagnosis, treatment, and prevention within the area of ‘Injury’ (Pharmacological and Physiological Sciences Branch).