Inflammation is a major component in the pathogenesis of brain injury during stroke. Cell signaling pathways prominently involved in the inflammatory cascade are initiated through Toll-like receptors (TLRs). Thus TLRs may be novel targets for stroke therapeutics. TLR4 is responsible for ischemic tolerance induced by systemic administration of lipopolysaccharide (LPS). Potential deleterious side effects preclude translation. We have found that additional TLRs (TLR7 &TLR9) are also potent targets to induce preconditioning against stroke. Pretreatment with the TLR9 agonist, CpG ODNs, reprograms cell signaling during subsequent stroke and the resultant inflammatory cell signaling is changed to potent neuroprotection. CpG ODNs are well tolerated in humans offering rapid translation as pre-stroke treatment for patients at high risk (e.g. new TIA, pending CABG surgery). Here we propose to characterize this novel prophylactic stroke therapy and demonstrate the efficacy and immune cell activation in the setting of stroke. We will address the potential mechanisms that underlie neuroprotection and whether these mechanisms act systemically and/or are located in the CNS as human treatments may optimally be directed systemically or centrally.
Aim 1. Characterization of neuroprotection induced by the TLR9 agonist, CpG ODNs.
Aim 3. Determine whether the primary inducers and effectors of LPS preconditioning are shared by imiquimod and CpG preconditioning pathways.
Aim 2. Determine the relative contribution of CNS resident cells and systemic hematopoietic cells to TLR9 induced neuroprotection.
Aim 3. Determine whether TNFa and IFNb are critical effectors of ischemic tolerance elicited by TLR9 (CpG) preconditioning.
Aim 4. Determine whether CpG preconditioning reprograms the response to stroke through modulation of TLR signaling pathways.

Public Health Relevance

Protecting the brain against future stroke. Here we describe a treatment by which we can modify chemical events in brain so that protection will result if a stroke were to occur. With this treatment, the damaging domino effect in brain, caused by the stroke that leads to profound brain injury, can be redirected towards a neuroprotective cascade. Studies here will test whether such treatment can be developed into a potential treatment for patients at high risk of stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062381-04
Application #
8320174
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$330,138
Indirect Cost
$115,763
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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
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
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
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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