The inflammatory reaction associated with cerebral ischemia contributes to the acute phase of ischemic brain damage raising the possibility that suppressing inflammation could be of therapeutic value in ischemic stroke. However, our understanding of post- ischemic inflammation is not sufficient to direct therapeutic interventions. In particular, the upstream events initiating and coordinating the expression of the cytokines and adhesion molecules that drive the infiltration of inflammatory cells into the brain remain poorly defined. The type-B scavenger receptor CD36, a multifunctional receptor expressed in blood cells, endothelium and microglia, is activated by a broad array of ligands, including "danger associated molecular pattern molecules" (DAMPs) released by tissue damage. Studies during the previous funding period have established that CD36-null mice have a profound attenuation of the post-ischemic expression of inducible nitric oxide synthase and cellular infiltration, and are protected from cerebral ischemic damage. Therefore, the central hypothesis of this application is that CD36 is a key upstream receptor that is activated by stress signals and enhances brain injury by promoting the post-ischemic accumulation of inflammatory cells in the brain. We will test the following specific hypotheses: (1) CD36 is required for the post-ischemic entry into the brain of selected inflammatory cell populations that influence the outcome of cerebral ischemia;(2) CD36 induces a pattern of cell-specific expression of cytokines and adhesion molecules that drives the brain infiltration of selected inflammatory cells;(3) CD36 expression in endothelium and microglia, not hematogenous cells, triggers the cellular and molecular events driving the component of post-ischemic inflammation that depends on CD36. We will test these hypotheses using state-of-the-art approaches for induction of transient focal cerebral ischemia with assessment of histological and behavioral outcome in mice. Flow cytometry, bone marrow chimeras and mice with cell specific inactivation of CD36 will be used to pinpoint the specific cell type(s) involved in the response.
Stroke caused by insufficient blood flow to the brain (ischemic stroke) is a leading cause of brain damage and death, but there is a paucity of therapies to protect the brain from its devastating effects. CD36 is emerging as a critical upstream sensor and coordinator of the inflammatory reaction that plays a key role in the brain damage caused by cerebral ischemia. The proposed studies will pinpoint the specific cells expressing CD36 and will provide a therapeutic target to counter the deleterious effects of the inflammation associated with stroke.
|Kuceyeski, Amy; Navi, Babak B; Kamel, Hooman et al. (2016) Structural connectome disruption at baseline predicts 6-months post-stroke outcome. Hum Brain Mapp 37:2587-601|
|Garcia-Bonilla, Lidia; Faraco, Giuseppe; Moore, Jamie et al. (2016) Spatio-temporal profile, phenotypic diversity, and fate of recruited monocytes into the post-ischemic brain. J Neuroinflammation 13:285|
|Fu, Ying; Liu, Qiang; Anrather, Josef et al. (2015) Immune interventions in stroke. Nat Rev Neurol 11:524-35|
|Navi, Babak B; Reiner, Anne S; Kamel, Hooman et al. (2015) Association between incident cancer and subsequent stroke. Ann Neurol 77:291-300|
|Hochrainer, Karin; Jackman, Katherine; Benakis, Corinne et al. (2015) SUMO2/3 is associated with ubiquitinated protein aggregates in the mouse neocortex after middle cerebral artery occlusion. J Cereb Blood Flow Metab 35:1-5|
|Gupta, Ajay; Gialdini, Gino; Lerario, Michael P et al. (2015) Magnetic resonance angiography detection of abnormal carotid artery plaque in patients with cryptogenic stroke. J Am Heart Assoc 4:e002012|
|Kuceyeski, Amy; Navi, Babak B; Kamel, Hooman et al. (2015) Exploring the brain's structural connectome: A quantitative stroke lesion-dysfunction mapping study. Hum Brain Mapp 36:2147-60|
|Hochrainer, Karin; Pejanovic, Nadja; Olaseun, Victoria A et al. (2015) The ubiquitin ligase HERC3 attenuates NF-ÎºB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation. Nucleic Acids Res 43:9889-904|
|Garcia-Bonilla, Lidia; Racchumi, Gianfranco; Murphy, Michelle et al. (2015) Endothelial CD36 Contributes to Postischemic Brain Injury by Promoting Neutrophil Activation via CSF3. J Neurosci 35:14783-93|
|Jackman, Katherine; Iadecola, Costantino (2015) Neurovascular regulation in the ischemic brain. Antioxid Redox Signal 22:149-60|
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