Research Project
10125721
The focus of research in aneurysmal subarachnoid hemorrhage for the last 30 years has been on understanding the pathophysiology of vasospasm and attempts to ameliorate it. Unfortunately, even when vasospasm is effectively treated, there is no improvement in death or disability. Subsequently, a novel concept and more effective endpoint for clinical trials emerged over the last 10 years: delayed cerebral ischemia (DCI), referring to new infarctions causing focal neurological deficits. Studies have shown that the occurrence of DCI is independently associated with morbidity, at least. The causes of DCI remains uncertain, but we believe that a focus on the cerebral inflammatory response (CIR) to the persistent heme burden that remains is a likely culprit for the initiation of DCI. While many independent associations for DCI exist, none account for the CIR in any way. Perhaps a focus on expedited hematoma resolution as well as finding some measure of the CIR to increase accuracy of DCI prediction is in order. Based on our mouse model of SAH, we found that the tissue resident macrophages of the brain are responsible for the majority of the CIR as well as for hematoma resolution. In our proposal, we use each individual patient?s cerebrospinal fluid (CSF) macrophages that are of tissue resident origin to study DCI and hematoma resolution. Specifically, we put these special macrophages in contact with a human neuronal cell line as a way to predict whether or not a patient might have DCI. We use flow cytometry to determine if the macrophages in the CSF are phagocytosing significant amounts of red blood cells to determine if the hematoma will resolve faster, and if this results in less DCI. We believe that these studies could provide a personalized approach to predicting DCI and hematoma resolution based on an individual?s innate immune profile. If validated in a prospective trial, these cell-based assays could be used to empirically discover new therapeutic targets for agents that could enhance RBC phagocytosis and reduce neuronal apoptosis by CSF macrophages, in an example of ?bedside to bench? reverse translation.
