Endogenous Mechanisms of Neuroprotection. See our projects.
The focus of the Stenzel-Poore lab is to develop novel therapeutic treatments for ischemic brain injury that utilize the brain’s own endogenous mechanisms to provide powerful neuroprotection. Brain ischemia is a leading cause of morbidity and mortality in the United States. Current therapeutic approaches aim to mitigate the extent of damage and promote repair once injury has occurred. However, many patients at high risk of ischemic injury can be identified in advance, providing the opportunity for antecedent neuroprotective intervention. Through the use of in vitro and in vivo models of brain ischemic injury, we have shown that activation of Toll-like receptors (TLR), a family of innate immune receptors, prior to an ischemic event provides significant protection against brain injury. Our longstanding NINDS R01-funded program has made significant advances in this field through mechanism-based studies. We were the first to discover that preconditioning reprograms the brain’s response to ischemia producing an endogenous neuroprotective genomic signature that is dependent on interferon-associated genes. These findings changed the field by identifying interferon-mediated pathways as integral parts of endogenous protection. Our recent findings revealed critical interactions between circulating cells and the neurovascular unit that coordinate neuroprotection mediated by TLR preconditioning. In addition to these studies we have identified several promising neurotherapeutic TLR-based strategies to protect the brain from injury. We are now advancing these TLR agonists through a translational research program that capitalizes on our novel non-human primate model of stroke, developed as a joint venture between our lab and the Oregon National Primate Research Center. Using this model, we have been the first to show neuroprotective efficacy using preconditioning with a TLR agonist. We have shown in the rhesus macaque, that preconditioning with a TLR9 agonist provides significant protection against a subsequent cerebrovascular ischemic event, demonstrated by both a reduction in infarct size and neurological deficit. These findings have enabled us to initiate IND studies in preparation for Phase I clinical trials with human patients. These translational studies are dependent on our expert stroke team of multi-disciplinary investigators who bring state of the art competencies in neurosurgery, primate behavior, multi-modal imaging, drug testing, feasibility studies and biomarker development.