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)
National Institute of Neurological Disorders and Stroke (NINDS)
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; Stevens, Susan L; Stenzel-Poore, Mary P (2016) Role of Circulating Immune Cells in Stroke and Preconditioning-Induced Protection. Acta Neurochir Suppl 121:39-44
Gesuete, Raffaella; Christensen, Sara N; Bahjat, Frances R et al. (2016) Cytosolic Receptor Melanoma Differentiation-Associated Protein 5 Mediates Preconditioning-Induced Neuroprotection Against Cerebral Ischemic Injury. Stroke 47:262-6
Vartanian, Keri B; Mitchell, Hugh D; Stevens, Susan L et al. (2015) CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury. J Cereb Blood Flow Metab 35:257-66
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
Lanekoff, Ingela; Stevens, Susan L; Stenzel-Poore, Mary P et al. (2014) Matrix effects in biological mass spectrometry imaging: identification and compensation. Analyst 139:3528-32
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
Gesuete, Raffaella; Packard, Amy E B; Vartanian, Keri B et al. (2012) Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro through type I interferon signaling. J Neurochem 123 Suppl 2:75-85
Packard, Amy E B; Leung, Philberta Y; Vartanian, Keri B et al. (2012) TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning. J Cereb Blood Flow Metab 32:2193-200
McDermott, Jason E; Vartanian, Keri B; Mitchell, Hugh et al. (2012) Identification and validation of Ifit1 as an important innate immune bottleneck. PLoS One 7:e36465

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