Dr. Paul is an Associate Professor of Neurology and Neurosciences. He received his PhD degree from the Indian Institute of Chemical Biology, India and did his post-doctoral training at Yale University School of Medicine. His federally funded research program is aimed at understanding the cellular and molecular basis of both acute and chronic neurological disorders related to excitotoxicity. His laboratory is particularly interested in determining the role of protein tyrosine phosphatases in the regulation of signaling pathways in cerebral ischemia, aging and hypertension as well as development of strategies for intervention.
- Glutamatergic signaling pathways in the CNS
- Protein tyrosine phosphatases and neurological disorders
- Oxidative stress and aging
Research in my laboratory focuses on understanding the cellular mechanisms of neuronal injury and development of strategies for intervention in neurological disorders related to excitotoxicity and oxidative stress.
Excitotoxicity refers to the deleterious effects of overstimulation of the neurotransmitter glutamate. Excessive neuronal Ca2+ entry and activation of series of Ca2+ dependent enzymes along with enhanced oxidative stress induce excitotoxic neuronal cell death. Excitotoxicity is known to be involved in several neurological diseases, including focal cerebral ischemia, traumatic brain injury, Huntington’s chorea and amyotrophic lateral sclerosis. To evaluate the role of the brain-specific tyrosine phosphatase STEP (STriatal Enriched Phosphatase) in neurological disorders related to excitotoxicity we use a broad range of interdisciplinary approaches, including neuronal cultures, rodent models of cerebral ischemia, mouse genetic models, biochemical, molecular, immunohistochemical, behavioral and magnetic resonance imaging strategies.
Our earlier work showed that the activity and stability of STEP is tightly regulated by several post-translational modifications that include phosphorylation, polyubiquitination and intermolecular dimerization. The neurotransmitters dopamine and glutamate play critical roles in regulating the activity of STEP. Additional studies using cell culture models of excitotoxicity and hypoxia-reoxygenation injury as well as an animal model of focal cerebral ischemia demonstrated a role of STEP in neuroprotection through down regulation of p38 mitogen activated protein kinase, a stress-activated kinase that is involved in neuroinflammation and death.
Our current focus is to elucidate additional signaling pathways that regulate the activity of STEP and identify novel target molecules that are modulated by STEP signaling. We are also evaluating whether a STEP-derived peptide could reduce the consequences of ischemic injury and impart long-term neuroprotection. The STEP KO mice are also being used to evaluate the molecular basis of exacerbated ischemic brain injury in the absence of STEP. Another interest of the laboratory is to evaluate the role of STEP in regulating the key pathways affected by oxidative stress during aging and age-associated increase in hypertension.
education and training
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