Traumatic brain injury, both from direct trauma to the brain and as a sequela of ischemic or hemorrhagic infarction are associated with a significant rate of morbidity, mortality and cost to both patients and the healthcare system. Hemorrhagic infarcts (such as aneurysmal subarachnoid hemorrhage and intraventricular hemorrhage) are rare but devastating complications of arterial rupture. Despite significant effort, there has been little improvement in the outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH) or intraventricular hemorrhage (IVH). Given the predictable temporal course of these brain injuries, they are ideal candidates for biomarker identification. A biomarker for detection o 'at risk'patients and a prognostic indicator of delayed neurological deficit would vastly improve current treatments and increase our understanding of underlying pathological events. This information would immediately lead to the implementation of new therapeutic strategies. Research over the last several years has identified extracellular RNAs (exRNA) as a potential source of biomarkers. New technology, such as next generation sequencing (NGS), has made it possible to sensitively and quantitatively assay small amounts of RNA contained in clinically attainable volumes of biofluids such as CSF and blood plasma. In the first two years of this grant, we propose to sequene the exRNA (miRNA and total RNA) from both the CSF and plasma of patients who present with aSAH and the plasma and CSF from premature infants born with IVH. aSAH samples were collected daily~ the volume of sample available will allow us not only to sequence the total RNA including miRNAs, but will permit us to explore unique enrichment strategies in years 3-5 of this grant~ we will examine specific RNAs associated with microvesicles in both CSF and plasma. We have both the daily clinical evaluations of these patients as well as their outcomes (25 subjects in all). We will use these samples to identiy RNA markers that predict onset of vasospasm and the severity of delayed neurological deficits. We also have CSF and plasma samples collected every other day from premature infants with grade III-IV IVH that had reservoirs put in place to evacuate blood and excess CSF. We also have the clinical outcomes from the infants, whether or not they developed hydrocephalus, the need for a permanent shunt, and an 18 month assessment of developmental delays or disabilities. In years 3-5, we will continue to collect samples in collaboration with both of our clinical partners. At that time, we will switch from our discovery platform, the Illumina HiSeq 2000 that has high depth of sequencing coverage, to the Illumina MiSeq for validation. Once the discovery phase is complete and potential biomarkers identified, validation can be carried out on the MiSeq's faster fluidics, imaging, and shortened run times without changing chemistries between the discovery and validation phases.

Public Health Relevance

The purpose of this research is to identify a biomarker to predict complications of brain injury, allowing us to decrease the severity and number of poor outcomes. The predictable temporal onset of brain injuries associated with intraventricular hemorrhage and aneurysmal subarachnoid hemorrhage make them highly amenable to the identification of a biomarker that can be used to alter and monitor treatment strategies.

National Institute of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
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Special Emphasis Panel (ZRG1-GGG-R (51))
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Tagle, Danilo A
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Translational Genomics Research Institute
United States
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Kalani, M Yashar S; Siniard, Ashley L; Corneveaux, Jason J et al. (2016) Rare Variants in Cardiomyopathy Genes Associated With Stress-Induced Cardiomyopathy. Neurosurgery 78:835-43
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Kalani, M Yashar S; Ramey, Wyatt; Albuquerque, Felipe C et al. (2014) Revascularization and aneurysm surgery: techniques, indications, and outcomes in the endovascular era. Neurosurgery 74:482-97; discussion 497-8