The brain-enriched tyrosine phosphatase STEP is emerging as a novel target for modulating neurological disorders related to excitotoxicity, including stroke. STEP is expressed in neurons of the cortex, hippocampus, and striatum, and participates in neuronal cell survival following an excitotoxic insult. The neurotransmitter glutamate plays a critical role in regulating the activity of STEP and our recent studies indicate that rapid activation of endogenous STEP can provide initial neuroprotection against ischemic injury. However we found that degradation of the active STEP over time allows activation of deleterious ischemic cascades responsible for ischemic brain injury. Restoration of STEP signaling with intravenous administration of a stable STEP derived peptide (TAT-STEP-myc peptide) provides significant protection against ischemic brain injury measured at 24 hr. The long-term goal of our current research is to determine whether the STEP signaling pathway is a potential target for treatment of ischemic stroke and related neurological disorders. The objective of this particular application is to determine whether interventions to restore STEP signaling can facilitate long- term protection from ischemia-induced brain damage and improve functional recovery in both young and aging animals. The central hypothesis is that the STEP signaling pathway, through its concerted action on multiple deleterious cascades of ischemic injury can evolve as a unique and effective target for stroke therapy. The proposed study will use magnetic resonance imaging (MRI) and behavioral studies for longitudinal evaluation of ischemic brain injury and neurological outcome, and determine the therapeutic time window of protection. To understand the molecular mechanism(s) of neuroprotection, the study will delineate the deleterious cascades that are suppressed by STEP. Furthermore the study will investigate the mechanism(s) involved in age-dependent increase in oligomerization and subsequent inactivation of STEP. The study will also evaluate the ability of an oligomerization-resistant STEP peptide in reducing ischemic injury in aging animals. The development and use of novel, stable, brain-permeable and degradation-resistant agent as well as the use of STEP KO mice and aging animals as tools to establish the neuroprotective potential of a tyrosine phosphates in ischemic brain injury is innovative. We rationalize that these studies will advance our understanding of the molecular mechanisms involved in the regulation of STEP and its function in both young and aging brain. The proposed research is significant since it will provide the first evidence for the role of a tyrosine phosphatase in limiting ischemic brain injury and may provide a much-needed target for therapeutic intervention in ischemic stroke.

Public Health Relevance

The proposed research is relevant to public health because the findings about the role of the brain-enriched tyrosine phosphatase STEP in neuroprotection can help in the development of potentially novel therapeutic agents for treatment of ischemic stroke. The project is relevant to the part of NIND's mission that pertains to advance significantl our fundamental knowledge about the neuroprotective pathways that are activated in the brain during ischemia and the application of that knowledge to reduce the burden of stroke dependent disability and mortality.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Bosetti, Francesca
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University of New Mexico Health Sciences Center
Schools of Medicine
United States
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Poddar, Ranjana; Chen, Alexandria; Winter, Lucas et al. (2017) Role of AMPA receptors in homocysteine-NMDA receptor-induced crosstalk between ERK and p38 MAPK. J Neurochem 142:560-573
Poddar, Ranjana; Rajagopal, Sathyanarayanan; Winter, Lucas et al. (2017) A peptide mimetic of tyrosine phosphatase STEP as a potential therapeutic agent for treatment of cerebral ischemic stroke. J Cereb Blood Flow Metab :271678X17747193
Poddar, Ranjana; Rajagopal, Sathyanarayanan; Shuttleworth, C William et al. (2016) Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP: MOLECULAR BASIS FOR ZN2+-INDUCED ERK MAPK ACTIVATION. J Biol Chem 291:813-25
Rajagopal, Sathyanarayanan; Deb, Ishani; Poddar, Ranjana et al. (2016) Aging is associated with dimerization and inactivation of the brain-enriched tyrosine phosphatase STEP. Neurobiol Aging 41:25-38
Deb, Ishani; Manhas, Namratta; Poddar, Ranjana et al. (2013) Neuroprotective role of a brain-enriched tyrosine phosphatase, STEP, in focal cerebral ischemia. J Neurosci 33:17814-26
Poddar, Ranjana; Paul, Surojit (2013) Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death. J Neurochem 124:558-70
Deb, Ishani; Poddar, Ranjana; Paul, Surojit (2011) Oxidative stress-induced oligomerization inhibits the activity of the non-receptor tyrosine phosphatase STEP61. J Neurochem 116:1097-111
Mukherjee, Saibal; Poddar, Ranjana; Deb, Ishani et al. (2011) Dephosphorylation of specific sites in the kinase-specificity sequence domain leads to ubiquitin-mediated degradation of the tyrosine phosphatase STEP. Biochem J 440:115-25
Poddar, Ranjana; Deb, Ishani; Mukherjee, Saibal et al. (2010) NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death. J Neurochem 115:1350-62
Paul, Surojit; Connor, John A (2010) NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling. J Neurochem 114:1107-18