The brain-enriched and neuron-specific tyrosine phosphatase STEP is emerging as a novel target for modulating neurological disorders related to excitotoxicity. STEP is expressed in the cortex, striatum and hippocampus, and the activity of STEP is regulated by the neurotransmitters dopamine and glutamate. Using in vitro models of ischemia and an animal model of acute ischemic stroke we have shown that availability of active STEP is a key determinant of the extent of neuronal injury and ischemic brain damage. Our preliminary findings provide compelling evidence that oxidative stress associated with hypertension, the most prevalent comorbid condition in stroke patients, leads to significant loss of function of endogenous STEP. We also found that ischemic insult in hypertensive rats is associated with an increase in the level of a neuron-specific chemokine, CX3CL1 and exacerbation of brain injury. The objective of this proposal is to elucidate the mechanism(s) underlying the release of soluble CX3CL1 and its effect on stroke outcome under hypertensive condition. Our central hypothesis is that the cleavage and release of CX3CL1 is regulated by STEP, and loss of STEP function under hypertensive condition leads to excessive release of CX3CL1 following an ischemic insult resulting in augmentation of inflammatory responses through infiltration and activation of peripheral leukocytes. The proposed study will use wild-type and STEP knockout mice to delineate the mechanism of regulation of CX3CL1 by STEP. To evaluate the role of CX3CL1 in enhancing post-ischemic inflammatory respnse, we will utilize STEP KO mice, CX3CL1 KO mice as well soluble CX3CL1 overexpressing transgenic mice in the presence or absence of endogenous CX3CL1. Furthermore the study will delineate the mechanisms underlying the loss of STEP function under hypertensive condition and its implication for post- ischemic inflammation involving CX3CL1. Magnetic resonance imaging (MRI) and behavioral studies will be used for longitudinal evaluation of the extent of ischemic brain injury and behavioral deficits under hypertensive condition, and determine the efficacy, therapeutic time window and optimal dose of a STEP-derived peptide (TAT-STEP-myc) to confer neuroprotection. The use of STEP and CX3CL1 KO mice as well as CX3CL1 overexpressing transgenic mice, hypertensive rats and a brain-permeable and degradation-resistant STEP- derived peptide as tools to establish the role of STEP as a modulator of post-ischemic inflammatory response is innovative. We rationalize that understanding the role of STEP in limiting post-ischemic inflammatory response will help in the development of novel interventions for stroke therapy under comorbid conditions. The proposed research is significant since it will provide the first evidence for the role of a tyrosine phosphatase in neuroimmune communication and could have far reaching consequences for neurological disorders associated with oxidative stress and inflammation.

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 significantly 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