Stroke is a devastating clinical condition, for which an effective neuroprotective treatment is currently unavailable. In the previous funding period, we have investigated the role of mitochondrial damage in models of cerebral ischemia/reperfusion. Our results support the current concept that mitochondrial-dependent programmed cell death (PCD) and necrosis-triggered neuroinflammation via microglial overactivation are two important mechanisms that additively contribute to ischemic brain injury. Thus, interventions capable of alleviating both neuronal PCD and neuroinflammation during the acute stage may lead to effective neuroprotective therapies for stroke. Apoptosis signal-regulating kinase 1 (ASK1) triggers neuronal PCD via the mitochondrial pathway and may function as an essential component of signaling cascade during microglial activation. The dual functions of ASK1 in neurons and microglia present it as a novel interventional target for stroke. ASK1 is a 160-kDa serine/threonine protein kinase that activates both JNK and p38 MAPK pathways by phosphorylating MKK4/MKK7 and MKK3/MKK6, respectively. ASK1 is activated in cultured neurons by oxidative stress, DNA damage, or ER stress, and its activation has also been detected in vivo in models of cerebral ischemia. However, the signaling mechanisms underlying ASK1 activation in the context of ischemic injury are poorly understood. Furthermore, the direct evidence for a pathological role of ASK1 in ischemic brain injury is scant. This renewal proposal will test the overall hypothesis that specific inhibition of ASK1- dependent signaling cascade protects against ischemic neuronal injury via novel anti- apoptotic and anti-inflammatory mechanisms.
The specific aims are:
Aim 1. Test the novel hypothesis that ischemia triggers persistent ASK1 activation and neuronal PCD after ischemic injury via a positive-feedback signaling cascade involving oxidative stress and calcium deregulation, and ER stress.
Aim 2. Test the novel hypothesis that ASK1 activation contributes to ischemic brain injury via activation of microglia through ASK1/p38-dependent pro-inflammatory signaling.
Aim 3. Test the hypothesis that interventions via disrupting both ASK1/JNK- dependent pro-apoptotic signaling pathway and ASK1/p38-dependent microglial overactivation can confer prolonged neuroprotection and improve neurological outcome after cerebral ischemia. In summary, the proposed studies investigate a novel ASK1 pro-death signaling cascade in cerebral ischemia. A positive outcome of the project not only will have a high impact on enhancing our understanding of the basic molecular mechanisms of ischemic neuronal injury but also shed light on ASK1 as a potential therapeutic target for stroke.
Stroke is a devastating clinical condition for which an effective neuroprotective treatment is currently unavailable. We have identified ASK1 (apoptosis signal-regulating kinase 1) as a promising therapeutic target for the treatment of ischemic brain injury. The objective of this proposal is to investigate whether blockage of the ASK1 signaling cascade in brain can confer long-term neuroprotection and improve neurological outcomes after experimental stroke. This information will be valuable for future development of new therapeutic strategies for the treatment of stroke and, possibly, other neurological disorders.
|Cai, Wei; Yang, Tuo; Liu, Huan et al. (2017) Peroxisome proliferator-activated receptor ? (PPAR?): A master gatekeeper in CNS injury and repair. Prog Neurobiol :|
|Pu, Hongjian; Jiang, Xiaoyan; Wei, Zhishuo et al. (2017) Repetitive and Prolonged Omega-3 Fatty Acid Treatment After Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery. Cell Transplant 26:555-569|
|Wu, Yun; Wang, Jiayin; Shi, Yejie et al. (2017) Implantation of Brain-Derived Extracellular Matrix Enhances Neurological Recovery after Traumatic Brain Injury. Cell Transplant 26:1224-1234|
|Hu, Xiaoming; De Silva, T Michael; Chen, Jun et al. (2017) Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke. Circ Res 120:449-471|
|Zhang, Wenting; Chen, Ruiying; Yang, Tuo et al. (2017) Fatty acid transporting proteins: Roles in brain development, aging, and stroke. Prostaglandins Leukot Essent Fatty Acids :|
|Jiang, Xiaoyan; Andjelkovic, Anuska V; Zhu, Ling et al. (2017) Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol :|
|Cai, Mengfei; Zhang, Wenting; Weng, Zhongfang et al. (2017) Promoting Neurovascular Recovery in Aged Mice after Ischemic Stroke - Prophylactic Effect of Omega-3 Polyunsaturated Fatty Acids. Aging Dis 8:531-545|
|Yang, Yuanyuan; Liu, Huan; Zhang, Haiyue et al. (2017) ST2/IL-33-Dependent Microglial Response Limits Acute Ischemic Brain Injury. J Neurosci 37:4692-4704|
|Cai, Wei; Zhang, Kai; Li, Peiying et al. (2017) Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect. Ageing Res Rev 34:77-87|
|Shi, Yejie; Jiang, Xiaoyan; Zhang, Lili et al. (2017) Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury. Proc Natl Acad Sci U S A 114:E1243-E1252|
Showing the most recent 10 out of 105 publications