The University of Pittsburgh Brain Trauma Research Center has been investigating the molecular and cellular mechanisms of secondary brain injury (physiologic and neurochemical responses of the injured brain), and the effects of therapeutic moderate hypothermia since its inception in 1991. Our accomplishments include the following:

1. We have identified a subgroup of traumatic brain injured (TBI) patients who appear to benefit from therapeutic moderate hypothermia, and have defined several mechanisms through which this effect is realized.
2. We have begun to characterize the roles of posttraumatic oxidative stress, cytokines, growth factors, inducible nitric oxide synthase, and the bcl-2 family of proteins in secondary brain injury.
3. We have defined the significance of neutrophil accumulation following experimental TBI.

Completion of these studies has lead to an improved understanding of specific molecular mechanisms likely to be responsible for early and delayed neurologic dysfunction following TBI.

It has become clear to us that laboratory investigations of molecular mechanisms of secondary injury must be coordinated with clinical studies so that we can define the clinical relevance of those molecular mechanisms to functional outcome following human TBI. We are continuing with our investigations of basic molecular mechanisms responsible for secondary injury. These areas of investigation have arisen as logical extensions of our previous findings, and include the study of delayed oxidative stress and programmed cell death; the relationship of nitric oxide synthase as a potential endogenous neuroprotectant following TBI; the role of mesocortical dopamine systems in causing chronic functional and cognitive deficits; and the role of poly(ADP-ribose) polymerase as a mediator of oxidative DNA damage and apoptosis.

Special emphases has been placed on the systematic acquisition of human cerebral spinal fluid, dialysate samples of extracellular fluid, and brain tissue for use in our primary investigations. Because of this we will be able to correlate the findings of our primary investigations with human TBI and determine their relative importance in effecting neurologic outcome. In this way, the completion of our specific aims will help to define critical molecular mechanisms of secondary brain injury and identify treatments most likely to be beneficial to TBI patients.