Brain ischemia is one of the leading causes of morbidity and mortality in the United States, and many cases of ischemia are secondary to cardiovascular surgery. Pretreatment or preconditioning with a Tol-like Receptor agonist, LPS, induces a protective response to ischemic injury referred to as ischemic tolerance. This competitive renewal application seeks to elucidate the molecular events that define ischemic tolerance induced by LPS preconditioning. Our previous research revealed a novel genomic fingerprint that implicates type I interferons (IFNs) as primary effectors of LPS induced tolerance to ischemic injury. We discovered that the IFN transcription factor, IRF3 is required for LPS preconditioning and our recent preliminary work suggests that the IFN transcription factor, IRF7 may also be required. In addition we have found that the IFN genomic fingerprint extends to ischemic protection of the brain induced by two other preconditioning stimuli: a TLR9 ligand, unmethylated CpG ODNs and low dose ischemia thus broadening its importance. The appearance of a novel IFN fingerprint in neuroprotection supports a new working model of preconditioning in which Toll-like receptors are the central feature. Elucidation of the function of the IFN response may provide insight into the mechanism of TLR induced prophylactic treatment for stroke and lead to the development of a new TLR induced pathway of acute neuroprotection that by-passes the need for prior preconditioning. These findings have led us to hypothesize that LPS preconditioning induces neuroprotection through IRF3/IRF7 driven expression of a core set of genes that result in complimentary pathways of neuroprotection. We shall test the precepts of this model and its therapeutic potential in three aims:
Aim 1. Elucidate the function of transcription factors IRF3 and IRF7 in TLR-induced neuroprotection.
Aim 2. To determine the mechanism by which the IFN fingerprint confers neuroprotection in response to ischemic injury.
Aim 3. Test whether direct activation of IRF3/7 in the acute setting of stroke leads to ischemic neuroprotection.

Public Health Relevance

Stroke is a leading cause of morbidity and mortality in the United States. Brain injury from loss of blood flow can occur secondary to cardiovascular surgery. Prophylactic treatment of patients undergoing these surgeries would help reduce the risk of severe cognitive decline associated with these events. This proposal examines the molecular mechanisms of neuroprotection induced via preconditioning with the toll-like receptor ligand, LPS, in the pursuit of therapeutically relevant treatments to benefit patients who are at risk of stroke or brain injury related to cardiovascular surgery.

National Institute of Health (NIH)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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Oregon Health and Science University
Schools of Medicine
United States
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Gesuete, Raffaella; Kohama, Steven G; Stenzel-Poore, Mary P (2014) Toll-like receptors and ischemic brain injury. J Neuropathol Exp Neurol 73:378-86
Stevens, Susan L; Vartanian, Keri B; Stenzel-Poore, Mary P (2014) Reprogramming the response to stroke by preconditioning. Stroke 45:2527-31
Bahjat, Frances R; Gesuete, Raffaella; Stenzel-Poore, Mary P (2013) Steps to translate preconditioning from basic research to the clinic. Transl Stroke Res 4:89-103
Leung, Philberta Y; Stevens, Susan L; Packard, Amy E B et al. (2012) Toll-like receptor 7 preconditioning induces robust neuroprotection against stroke by a novel type I interferon-mediated mechanism. Stroke 43:1383-9
Packard, Amy E B; Hedges, Jason C; Bahjat, Frances R et al. (2012) Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury. J Cereb Blood Flow Metab 32:242-7
Stevens, Susan L; Leung, Philberta Y; Vartanian, Keri B et al. (2011) Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury. J Neurosci 31:8456-63
McDermott, Jason E; Archuleta, Michelle; Stevens, Susan L et al. (2011) Defining the players in higher-order networks: predictive modeling for reverse engineering functional influence networks. Pac Symp Biocomput :314-25
Vartanian, Keri B; Stevens, Susan L; Marsh, Brenda J et al. (2011) LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury. J Neuroinflammation 8:140
Bahjat, Frances Rena; Williams-Karnesky, Rebecca L; Kohama, Steven G et al. (2011) Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke. J Cereb Blood Flow Metab 31:1229-42
Marsh, Brenda; Stevens, Susan L; Packard, Amy E B et al. (2009) Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. J Neurosci 29:9839-49

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