Microglial Signal Transduction in Fever and Vasospasm after Subarachnoid Hemorrha

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DESCRIPTION (provided by applicant): Dr. Khalid Hanafy, an MD, PhD, presents a 5 year career development plan to investigate the role of microglia and inflammatory signal transduction pathways in the production of fever and vasospasm after subarachnoid hemorrhage. Thirty thousand Americans have aneurysmal subarachnoid hemorrhage (aSAH) each year. Currently therapy for these patients is limited, and thus the prognosis for aSAH is dismal. In aSAH, fever and vasospasm, otherwise known as delayed cerebral ischemia, merit further study because both are predictors of poor outcome in retrospective patient populations. An overwhelming majority of aSAH patients have either fever or vasospasm, and, as a whole, more than 40% or 12,000 aSAH patients die each year. Because fever and vasospasm are the only modifiable risk factors for a poor outcome, they are an important target in the future treatment of aSAH. To this end, elucidation of the signal transduction pathways that lead to central fever and vasospasm are critical to the development of novel therapeutics for this deadly disease. In models of neurodegenerative disease, intracerebral hemorrhage, and central fever; an important mediator of cerebral inflammation is the resident macrophage or microglia. The Specific aims of this project are: (1): To examine whether SAH induced in microglia-depleted mice have less central fever and less vasospasm than SAH in wild type mice. (2): To determine if the TLR4-MyD88 pathway is required for fever and vasospasm in SAH. (3): To assess whether central fever after SAH is mediated by the neuronal EP3 receptor. Dr. Hanafy, a neurointensivist, is well-qualified to study these questions with his background in molecular biology and small animal models. His studies of fever as they relate to subarachnoid hemorrhage are novel and will be well-supported by Dr. Clifford Saper, an expert in the neurobiological basis of fever. He will be trained in additional surgical techniques and data interpretation during this project. Furthermore, the candidate has scheduled frequent meetings with Dr. Saper to discuss progress on the project, in addition to a plan for career development. Dr. Hanafy's goal is to develop novel therapeutic avenues for the treatment of subarachnoid hemorrhage through better understanding of the molecular mechanisms that lead to fever and vasospasm after subarachnoid hemorrhage. To help him accomplish this goal, Dr. Hanafy has assembled an excellent panel of advisors to meet with him three times a year. They include Dr. Clifford Saper, Chairman of the Department of Neurology; Dr. Terry B. Strom, Director of Transplant Immunology; and Dr. William C. Aird, Director of the Center for Vascular Biology Research. Dr. Strom has published extensively in the role of inflammatory transduction pathways in transplant mediated phenomenon and Dr. Aird is researching different forms of hemorrhagic stroke and their effects on the endothelial cell. We are confident that Dr. Hanafy has the tools to complete his project as outlined and hope he will become a successful NIH funded investigator. PUBLIC HEALTH RELEVANCE: Even though a minority of the 795,000 strokes per year is due to aneurysmal subarachnoid hemorrhage (aSAH), it accounts for more than 50% of the annual direct cost of stroke per person and upwards of 68% mortality at one year. Vasospasm that leads to delayed cerebral ischemia requires further study because it occurs in 40% of aSAH patients. However, research targeting only vasospasm may not account for all clinical sequalae of aSAH that lead to poor outcome; such as fever, which also occurs in 40% of these patients. To develop novel Neuro-therapeutics for aSAH patients, the molecular mechanisms that lead to both fever and vasospasm need to be thoroughly understood to produce a complete picture of the pathophysiology of aSAH.