Targeting Glial HuR to Suppress Inflammation and Promote Neuroprotection in Acute Stroke

About This Grant

Stroke is a leading cause of disability and death with ischemic strokes (IS) accounting for more than 85% of strokes. After consideration of thrombolytics at presentation of IS, treatment of patients is limited to supportive care (e.g., blood pressure and glucose control) for neuroprotection. This represents a large gap in our management of patients with IS. The neuroinflammatory response after stroke is a major determinant of tissue injury and is triggered within minutes by activated microglia and astrocytes. These cells produce and secrete cytokines and vasoactive factors that exacerbate tissue injury either by direct cytotoxicity or indirectly by disruption of the blood brain barrier with increased vascular permeability, edema, and hemorrhagic transformation. The inflammatory cascade is further accelerated by glial production of chemokines which recruit peripheral immune cells, including neutrophils, monocytes, and T cells, within the acute phase of IS. Past failures in targeting neuroinflammation after IS likely stem from the multiple and overlapping pathways driving it. A major determinant of the glial inflammatory response is the RNA regulator, HuR, which promotes the expression of diverse pro-inflammatory mediators. Key drivers of inflammation after IS, such as IL-1β, TNF-α, COX-2, and iNOS, contain adenine- and uridine-rich elements (ARE) in the 3’ untranslated region to which HuR binds and positively regulates their expression. Our team has developed a novel class of small molecule HuR inhibitors that block induction of pro-inflammatory mediators in glial cells. Our preclinical studies indicate excellent and rapid penetration of SRI-42127 into the CNS after systemic administration. In middle cerebral artery (MCAO) models of IS, we observed significant reductions in IS volume after SRI-42127 treatment. We hypothesize that HuR drives a pro-inflammatory and toxic secretome in IS, initiated by glial cells, and then amplified by recruited peripheral immune cells. Furthermore, HuR inhibition will reduce secondary injury and improve functional outcome. We propose 3 aims: (1) Further characterize the beneficial effect of HuR inhibition by SRI- 42127 after IS, including aged mice, (2) Assess molecular and cellular mechanisms by which HuR inhibition improves recovery after IS, and (3) Assess the contribution of glial and macrophage HuR to neuroinflammation and secondary tissue injury after IS using mouse knockout models. The long term objectives are to gain mechanistic understanding of how HuR-mediated post-transcriptional regulation in microglia, astrocytes and other key cellular constituents impacts neuroinflammatory responses and secondary tissue injury after IS. The innovation of this proposal is the investigation into RNA regulation of inflammatory responses in glia and other immune cells (to date underexplored), including in aged models, and the development of a novel class of inhibitors for neuroprotection. The ultimate goal would be to fill a large clinical gap in the management of IS. The significance extends beyond IS as the same HuR-regulated pathways drive inflammation in other acute (e.g., traumatic brain injury or spinal cord injury) and chronic (e.g., ALS and Alzheimers) neurological diseases.