# Role of Brain Specific Tyrosne Phosphatase STEP in Neuroprotection and Death

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $503,383

## Abstract

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 inflammat...

## Key facts

- **NIH application ID:** 9963368
- **Project number:** 5R01NS059962-13
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Surojit Paul
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $503,383
- **Award type:** 5
- **Project period:** 2008-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963368

## Citation

> US National Institutes of Health, RePORTER application 9963368, Role of Brain Specific Tyrosne Phosphatase STEP in Neuroprotection and Death (5R01NS059962-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9963368. Licensed CC0.

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