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.
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.
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 11 publications