Stroke is among the top ten causes of death in children but has received disproportionally little attention. The developmental stage of the brain at the stroke onset plays key role in injury mechanisms. In humans, perinatal arterial stroke is frequent but is almost never recurrent, whereas childhood arterial ischemic stroke (CAIS) is less frequent but its recurrence rate is strikingly high. Emerging clinical data show that cerebral arteriopathy is strongly predictive of stroke recurrence and that recent viral infection predisposes to CAIS by sensitizing the vasculature. Leukocytes have been postulated to increase CAIS risk and its recurrence by serving as ultimate mediators of infection-induced cerebral arteriopathies. To understand how viral infection exacerbates CAIS, we established a novel age-appropriate model of childhood arteriopathy induced by viral infection via administration of a Toll-like receptor 3 ligand Poly-I:C in postnatal day 18 (P18) mice. To mimic CAIS, we established a novel age-appropriate childhood stroke model, transient middle cerebral artery occlusion (tMCAO) in P21 mice. We hypothesize that viral infection-induced arteriopathy exacerbates childhood stroke in myeloid cell- dependent manner. We will examine effects of viral infection at P18 in producing vascular inflammation, arteriopathy and changes leukocyte phenotypes (Aim 1), determine if inhibition of either leukocyte recruitment or neutrophil signaling attenuate infection-induced exacerbation of vascular inflammation and injury after childhood stroke (Aim 2), and determine the role of monocyte Vs. neutrophil signaling in enhancing disrupted brain connectivity after childhood stroke by preceding infection (Aim 3). We will utilize several pharmacological and genetic strategies in vivo to disrupt signaling or abolish trafficking of individual subsets of myeloid cells and use novel tools to examine vascular re-mapping in vivo in relation to changes in brain connectivity and long- term functional outcomes. In vessels isolated from juvenile brains following infection and/or stroke, we will further examine vascular inflammation and modes of endothelial activation. The use of reporter Lys-eGFP-ki mice and reporter mice with defective CCR2-mediated monocyte trafficking will enable visualizing myeloid cells, distinguishing them from brain immune cells, and identifying phenotypic leukocyte changes. Longitudinal multi-modal MRI will non-invasively delineate stroke severity, recurrence and hemorrhagic transformation enhanced by viral infection, and delineate changes in vessel architecture (MR angiography). We will examine effects in males and females because CAIS is more common in boys than in girls and protective role of innate immune receptors may be sex-dependent. Our unique ability to identify how to ameliorate childhood stroke by changing the leukocyte phenotypes following infection-triggered arteriopathy would critically advance the understanding of CAIS and identify new pharmacologic targets.
Stroke is among the top ten causes of death in children ages 1 month to 18 years old. Emerging clinical data show high recurrence rate of childhood arterial ischemic stroke, point to cerebral arteriopathy as strong predictor of stroke recurrence, up to 80% of cases, and show that recent infection?bacterial or viral? sensitizes the vasculature, increasing the risk of stroke and its recurrence. The proposed studies will identify novel mechanisms of infection-induced cerebral arteriopathy in injury exacerbation in a novel model of childhood stroke and discover new pharmacological targets to reduce brain injury in affected children.
|Salehi, Arjang; Jullienne, Amandine; Wendel, Kara M et al. (2018) A Novel Technique for Visualizing and Analyzing the Cerebral Vasculature in Rodents. Transl Stroke Res :|