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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045048-07
Application #
8337303
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2003-02-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$337,867
Indirect Cost
$99,235
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Li, Peiying; Mao, Leilei; Liu, Xiangrong et al. (2014) Essential role of program death 1-ligand 1 in regulatory T-cell-afforded protection against blood-brain barrier damage after stroke. Stroke 45:857-64
Zhang, Meijuan; Wang, Suping; Mao, Leilei et al. (2014) Omega-3 fatty acids protect the brain against ischemic injury by activating Nrf2 and upregulating heme oxygenase 1. J Neurosci 34:1903-15
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Wang, Guohua; Jiang, Xiaoyan; Pu, Hongjian et al. (2013) Scriptaid, a novel histone deacetylase inhibitor, protects against traumatic brain injury via modulation of PTEN and AKT pathway : scriptaid protects against TBI via AKT. Neurotherapeutics 10:124-42
Anne Stetler, R; Leak, Rehana K; Gao, Yanqin et al. (2013) The dynamics of the mitochondrial organelle as a potential therapeutic target. J Cereb Blood Flow Metab 33:22-32
Zhang, Meijuan; Wang, Haiying; Zhao, Jinbing et al. (2013) Drug-induced hypothermia in stroke models: does it always protect? CNS Neurol Disord Drug Targets 12:371-80

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