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Kelly
L. Jordan-Sciutto, Ph.D.
Associate Professor
Department of Pathology School of Dental Medicine
Rm
312, Levy Research Building
Phone 215-898-4196; FAX 215-573-2050
E-mail:
Jordan@path.dental.upenn.edu
Lab: http://www.dental.upenn.edu/depts/pathology/faculty-jordon.html
http://www.med.upenn.edu/camb/faculty/cgc/jordansciutto.html
Click here for selected publications since Dr. Jordan-Sciutto's arrival at Penn
RESEARCH INTERESTS
Assessing mechanisms of neuronal death (apoptosis vs necrosis in response to neuroinflammotry mechanisms and oxidative stress and protection by neurotrophins to gain insight into the molecular mechanisms underlying neuronal loss in neurodegenerative Disorders (i.e. Alzheimer's Disease, Parkinson's disease, and HIV encephalitis). We are specifically interested in the role of cell cycle proteins and transcriptional regulators in neuronal survival decisions.RESEARCH TECHNIQUES
Laser Confocal Microscopy, Primary neuronal cultures, Molecular and Cellular Aprroaches including Electrophoretic Mobility Shift Assay, Western blot, Cloning, In vitro expression, Transfection, etc, Immunohistochemistry, Immunofluorescence.RESEARCH SUMMARY
In our lab, we are interested in the common molecular mechanisms underlying neurodegenerative processes. We are specifically interested in the role of cell cycle proteins, the endogenous antioxidant response and a novel, developmentally regulated transcription factor, FAC1 in three neurodegenerative disorders, HIV encephalitis (HIVE), Alzheimer's disease (AD), and Parkinson's disease (PD).
While HIVE, AD, and PD exhibit different pathologic features, theories as to their etiology share common molecular mechanisms including change in the trophic factor environment, oxidative stress, and activation of CNS inflammatory components. We hypothesize that neuronal response to these neurodegenerative stimuli includes alterations in expression and/or activity of cell cycle proteins. We and others have shown that key regulators of cell cycle progression, Retinoblastoma susceptibility gene (pRb), E2F1, and p53, exhibit altered levels and patterns of expression in HIVE, PD, and AD. These changes are associated with areas of pathology suggesting a role in degenerative processes. In vitro models of neurodegeneration in each of these diseases also exhibit alterations in cell cycle protein subcellular localization. Currently, we are investigating the mechanism regulating the unique distribution of these proteins in neurons in response to neurodegenerative and neuroprotective stimuli and how this determines neuronal viability. Using primary neuroglial cultures stimulated with trophic factors, chemokines, dopamine, free radicals and beta-amyloid, we hope to define a common mechanism for neuronal loss in this subset of neurodegenerative disorders.
A developing area of research in our laboratory is the study of the endogenous anti-oxidant response and its failure to prevent accumulation of oxidative damage and neuronal loss in neurodegenerative disorders. The two proteins of direct interest to the laboratory are Keap1 and Nrf2. Nrf2 is a transcription factor that regulates the expression of the enzymes responsible for the antioxidant response. Normally, Nrf2 is bound in the cytoplasm by the Kelch ECH associated protein 1(Keap1). However, in response to oxidative stress, sulfhydryl groups on Keap1 become oxidized releasing Nrf2 for translocation into the nucleus. We are interested in whether these proteins exhibit insufficient or aberrant activity in neurodegenerative condition. The goal of these studies is to explore this pathway as a therapeutic target for neurodegenerative conditions. By enhancing the endogenous anti-oxidant response, neuronal toxicity may decrease leading to increased neuronal function in these patients.
A final area of interest for the laboratory is the functional characterization of a novel, developmentally regulated gene product, called FAC1. Preliminary studies indicate that FAC1 exhibits altered subcellular localization and expression during neurodegeneration, development and regeneration. Investigation of FAC1 function indicates that it can act as a site specific DNA binding protein and represses transcription through this site. Regulation of FAC1 directed transcription appear to be modulated by protein:protein interactions with other transcription factors (i.e. myc associated zinc finger protein (MAZ) and pRb) Using the dihybrid yeast screen, we have further demonstrated an interaction with Keap1 linking FAC1 to the oxidative stress response. This has interesting implications for FAC1 function and subcellular re-distribution to the cytoplasm. Finally, our preliminary observations suggest that overexpression of FAC1 can induce altered nuclear morphology consistent with apoptotic cell death. Current experimentation revolves around determining the roles of FAC1 and its interacting proteins in neuronal viability, differentiation and division. By understanding the activity of FAC1, we believe we will gain insight into the neuronal responses to neurodegenerative stimuli and identify a novel mechanism leading to neuronal loss.
KEY WORDS:
Cell Cycle, Oxidative Stress Response, Antioxidant Response, Neurodegeneration, Transcription, Primary Culture
