Paul J Lombroso MD
Elizabeth Mears and House Jameson Professor in the Child Study Center and Professor of Neurobiology and of Psychiatry; Director, Laboratory of Molecular Neurobiology
Translational Neuroscience; Identification of small molecule inhibitors of STEP; Child and adolescent psychiatry; Neuropharmacology
- Identification and characterization of STEP inhibitors.
- Characterization of the STEP knock-out mouse.
- Regulation of glutamate receptor trafficking by STEP.
- Role of STEP in different disorders
- Phosphorylation of STEP and function of phosphorylation at specific sites.
The laboratory focuses on mammalian learning and how these processes are disrupted in various neuropsychiatric disorders. We are interested in several disorders including fragile X syndrome, schizophrenia, Parkinson's disease, and Alzheimer's disease. Central to this investigation is a brain-specific protein tyrosine phosphatase called STEP and its role in regulating intracellular signaling.
Our earlier work showed that STEP regulates ERK1/2 and Fyn by dephosphorylating and inactivating them. STEP also regulates the cell surface expression of AMPA and NMDA glutamate receptors and leads to their internalization. Signals that lead to STEP inactivation potentiate learning, whereas signals that lead to the STEP activation oppose the development of synaptic plasticity. We use biochemical, molecular, immunocytochemical, and behavioral techniques in animal models to address the role that STEP plays in regulating aspects of learning.
On-going projects include the involvement of STEP in several neurospychiatric and neurodegenerative disorders including: Fragile X syndrome, Alzheimer's disease, Parkinson's disease, and schizophrenia. We are characterizing novel STEP inhibitors in animal models of these disorders and determining their ability to reverse cognitive and behavioral deficits; STEP's regulation of glutamate receptor trafficking; the regulation of STEP by ubiquitination and phosphorylation.
Extensive Research Description
The Lombroso Lab studies how we normally learn and how these processes are disrupted in various neuropsychiatric disorders. We are interested in a number of disorders including Tourette’s syndrome, obsessive-compulsive disorder, autism, as well as drug addiction and Alzheimer’s disease. Our work focuses on a brain-specific protein tyrosine phosphatase called STEP and its role in regulating intracellular signaling.
Studies have shown that STEP expression is disrupted in over 10 different disorders. Some have have elevated levels of STEP while others have lower expression. Thus the current model is that optimal levels of STEP are required for proper synaptic function. Substrates of STEP include the kinases ERK1/2, Pyk2 and Fyn and dephosphorylation inactivates these enzymesem. STEP also regulates the cell surface expression of AMPA and NMDA glutamate receptors, and leads to their endocytosis. Signals that lead to the inactivation of STEP potentiate learning, while signals that lead to the activation of STEP oppose the development of synaptic plasticity. We use biochemical, molecular, immunocytochemical, and behavioral techniques to address the role that STEP plays in regulating aspects of learning.