We have studied the clinical manifestations of cerebrovascular dysfunction caused by traumatic brain injury (TBI) during the past grant period. In patients, we observed a wide spectrum of cerebrovascular pathology, ranging from impaired pressure autoregulation which causes TBI patients to be more vulnerable to secondary ischemic insults, to severe global cerebral ischemia. The level of cerebral blood flow (CBF), especially within the first 12hr after injury, is strongly predictive of neurological outcome with each 10ml/100g/min increase in average cortical CBF resulting in a 3-fold increase in the chances of surviving to hospital discharge. In an experimental model of TBI, we have demonstrated that the hypoperfusion and dysfunction of blood flow regulation is caused at least in part by depletion of the nitric oxide (NO) produced by the endothelial isoform of NOS. We have also found that with the relative deficiency of NO, endothelium-derived hyperpolarizing factor (EDHF) becomes upregulated and may be an important endogenous mechanism for maintaining cerebral perfusion after TBI. The overall hypothesis of this proposal is that TBI causes a reduction in CBF in the early post-injury period that contributes to the brain damage by 2 mechanisms: 1-if the reduction in CBF is severe enough and lasts long enough, primary ischemic injury occurs 2-if the reduction in CBF is more modest, primary ischemic injury may not occur, but the brain is more susceptible to secondary ischemic insults. Trauma is the most common cause of death in the 1-44 yr age group, and the third most common cause for the entire US population. Trauma accounts for more loss of work life-years than cancer and cardiovascular diseases combined. Effective treatments for this important public health disorder are needed. Treatment of the cerebrovascular dysfunction caused by TBI could significantly improve neurological recovery following trauma. We will approach this problem with a combination of laboratory and clinical studies, each addressing some aspect of vascular dysfunction. The components of this proposal include three cores and the following four projects: Project 1. Effect of Erythropoietin on Vascular Dysfunction in Human TBI Project 2. Effect of Erythropoietin on Anemia and Need for Transfusion Project 3. EDHF Following Traumatic Brain Injury Project 4. Neuroprotection of Erythropoietin Signaling in TBI

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National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Hicks, Ramona R
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Baylor College of Medicine
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Rubin, Maria Laura; Chan, Wenyaw; Yamal, Jose-Miguel et al. (2017) A joint logistic regression and covariate-adjusted continuous-time Markov chain model. Stat Med 36:4570-4582
Vedantam, Aditya; Yamal, Jose-Miguel; Rubin, Maria Laura et al. (2016) Progressive hemorrhagic injury after severe traumatic brain injury: effect of hemoglobin transfusion thresholds. J Neurosurg 125:1229-1234
Aisiku, Imoigele P; Yamal, Jose-Miguel; Doshi, Pratik et al. (2016) The incidence of ARDS and associated mortality in severe TBI using the Berlin definition. J Trauma Acute Care Surg 80:308-12
Aisiku, Imo P; Yamal, Jose-Miguel; Doshi, Pratik et al. (2016) Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury. Crit Care 20:288
Lazaridis, Christos; Yang, Ming; DeSantis, Stacia M et al. (2015) Predictors of intensive care unit length of stay and intracranial pressure in severe traumatic brain injury. J Crit Care 30:1258-62
Yamal, José-Miguel; Benoit, Julia S; Doshi, Pratik et al. (2015) Association of transfusion red blood cell storage age and blood oxygenation, long-term neurologic outcome, and mortality in traumatic brain injury. J Trauma Acute Care Surg 79:843-9
Yamal, Jose-Miguel; Rubin, M Laura; Benoit, Julia S et al. (2015) Effect of Hemoglobin Transfusion Threshold on Cerebral Hemodynamics and Oxygenation. J Neurotrauma 32:1239-45
Yamal, Jose-Miguel; Robertson, Claudia S; Rubin, M Laura et al. (2014) Enrollment of racially/ethnically diverse participants in traumatic brain injury trials: effect of availability of exception from informed consent. Clin Trials 11:187-94
Robertson, Claudia S; Yamal, Jose-Miguel; Tilley, Barbara C (2014) Erythropoietin for traumatic brain injury--reply. JAMA 312:1929
Robertson, Claudia S; Hannay, H Julia; Yamal, José-Miguel et al. (2014) Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 312:36-47

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