Stroke is the fifth leading cause of death and the number one cause of long-term disability in the United States and worldwide. Hemorrhagic stroke constitute only 10-15% of total stroke types but is responsible for higher mortality rates and severe disabilities in stroke victims. Except surgical intervention, there is no effective treatment for the hemorrhagic brain injury. Thus, it is imperative to gain a better understanding of the pathways that are active after the hemorrhagic brain injury, in particular, inflammation. Cofilin, an actin associated protein controls cellular actin filament dynamics and reorganization by severing and depolymerizing actin filaments, and its remodeling in response to stress constitutes a basic adaptive mechanism. Studies have shown that cofilin dynamics control activation, migration and maturation of immune cells. In vitro preliminary studies involving cofilin siRNA and LPS-treated microglia showed reduced migration and decreased levels of NO, iNOS, COX2 and TNF-α, and the mechanism was found to be mediated by NF-κB and JAK-STAT pathway. Inhibiting cofilin activation with the siRNA in mice lead to decreased hematoma volume after intracerebral hemorrhage (ICH) due to lower levels of activated microglia and astrocytes. The central hypothesis of the proposal is that the cofilin signaling has a critical role in microglial activation after secondary injury induced by hemorrhagic brain injury. The proposed hypothesis will be addressed in two aims. Aim 1 will identify the role of cofilin in microglial activation and inflammation after hemin/thrombin exposure and the viability of primary neurons against conditioned medium derived from hemin/thrombin-activated microglia will be determined. Furthermore, cofilin downstream mechanisms will be elucidated by investigating NF-κB and JAK-STAT pathway. Aim 2 will identify the spatiotemporal pattern of cofilin in microglia over a protracted period of 14 days following ICH. The use of cofilin siRNA in mice will further ascertain the cofilin signaling in hemorrhagic brain injury mediated inflammation and neuronal death. The studies outlined in this proposal will provide insights on the role of cofilin in inflammation after hemorrhagic brain injury and the possible drug target for stroke therapy and will also provide training opportunities to aspiring undergraduate and graduate students interested in pursuing a career in the field of stroke research.
|Program type||AHA Institutional Research Enhancement Award (AIRE|
|Effective start/end date||07/01/2017 → 06/30/2019|