Genetics and Brain Ischemia in the Critically Ill

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DESCRIPTION (provided by applicant): This K24 Midcareer Investigator application describes the investigator's dedication to patient-oriented research, her experience in mentoring young researchers, and how this award would consolidate and develop these career commitments. The clinical focus of this application is the identification of genetic factors that will maximize cerebral perfusion in the critically ill patient with brain injury. The specific aims for this study are to: 1) describe the incidence of two common mitochondrial DNA (mtDNA) deletions (4799bp and 7436 bp) found in the cerebrospinal fluid (CSF) within the acute phase following brain injury; 2) determine whether the presence of mtDNA deletions are associated with cerebral profusion and metabolism and; 3) determine whether mtDNA deletions are associated with outcomes [Glasgow Outcomes Scale (GOS) and morality]. A descriptive comparative design will be used to determine whether the presence of mtDNA deletions decreases cerebral blood flow (CBF) and metabolism and results in poorer outcomes in critically ill brain injured patients. Two currently funded clinical research projects [Methods of Predicting Delayed Cerebral lschemia in Subarahnoid Hemorrhage, and The Effect of ApoE Genotype on Outcomes in Traumatic Brain Injured Adults] will provide the foundation for the mentoring activities that will enhance and develop young investigators' clinical research skills. They will also provide patient data on the timing, severity, type, and location of insult, demographic information, CSF for analysis, CBF and ischemia data, physiologic parameters and outcome evaluation. The long-term career objective is to identify profiles of patients based on genetic variation that will allow clinicians to design individualized interventions to maximize cerebral perfusion. The focus of inter-individual variations of patients with a severe brain injury will provide the opportunity to educate and mentor junior clinical investigators in the design, implementation, evaluation and dissemination of clinical studies that will, in the long term, improve patient outcomes. The studies are designed as a combination of basic and clinical science in order to directly apply the results to clinical practice. The incorporation of an individual' s genetic profile for maximizing cerebral perfusion provides an excellent platform for training the next generation of patient-oriented critical care researchers.