Kelly L. Jordan-Sciutto, Ph.D. Assistant Professor phone 215-898-4196 e-mail: jordan@path.dental.upenn.edu

Training:

• 1999-2000
  Research Associate in the laboratory of Dr. Clayton A. Wiley, University of Pittsburgh
• 1996-1999
  Post-doctoral Fellow in the laboratory of Dr. Robert Bowser University of Pittsburgh
• 1991-1996
  Ph.D. in Biochemistry and Molecular Biology with Dr. David J. Hall, Thomas Jefferson University

Research Interests:
Our laboratory investigates molecular mechanisms underlying neurodegenerative processes in the hopes of identifying common and unique players in determining neuronal survival among several neurodegenerative diseases. Currently we are focusing our research efforts on the role of cell cycle proteins, the endogenous antioxidant response and unfolded protein response 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 changes 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. To this end, we and others have shown that key regulators of cell cycle progression, Retinoblastoma susceptibility gene (pRb), E2F1, and/or 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. We are using both human tissue and in vitro models to uncover the role of cell cycle proteins, E2F1, MDMx (a p53 and E2F1 regulatory protein), and pRb in interpreting neuroprotective vs neurotoxic stimuli in primary human, rat, and mouse neuroglial cultures stimulated with trophic factors, chemokines, dopamine, free radicals, beta-amyloid, and HIV-infected macrophage supernatant. These studies are aimed at determining how cell cycle proteins regulate neuronal survival in response to varied and conflicting stimuli. In vitro findings are then used to assess potential roles for these proteins in animal models as well as autopsy tissue relevant to each neurodegenerative condition. Our investigation of E2F1 has resulted in the discovery of a role for this protein in activation of a calpain-dependent death pathway which has not been previously described. Interestingly, neurons responding to HIV-infected macrophage supernatants (our in vitro model of neuronal response to inflammatory infiltrate which mediates HIV encephalitis) activate calpain and increase E2F1 protein levels. One of our immediate lines of investigation is testing the hypothesis that E2F1 induces neuronal death in HIV encephalitis via calpain activation, a novel pathway.

A second 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 have recently shown that Nrf2 is aberrantly expressed in AD indicating it is not responding to oxidative stress in neurons of affected brain regions. Interestingly, Nrf2 does appear to be responding appropriately in neurons affected in PD. This has led us to hypothesize that the endogenous antioxidant response is aberrant in AD, but insufficient in PD. Our current studies focus on identifying differences in regulation of the endogenous antioxidant response in AD and PD. 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 on which our other two lines of investigation has converged is the role of the unfolded protein response (UPR). Induction of the unfolded protein response results in activation of Nrf2 and calpain, proteins activated in response to the endogenous antioxidant response and the E2F1 cell cycle protein respectively. This has led to our investigation of the UPR in neurodegenerative conditions. We are currently looking at pathways activated by the UPR in our various models of HIVE, AD, and PD. The key regulators of this response include pancreatic endoplasmic reticulum kinase (PERK), IRE1, and ATF6. We have already identified increased PERK and phosphorylation of PERK substrate eukaryotic initiation factor 2 a in AD tissue and an in vitro model of HIVE. This is consistent with findings by Ryu, E. J., et al. (2002, J. Neuroscience 22:10690) indicating a role for UPR in an in vitro PD model. However, our results indicate that Nrf2 a PERK substrate is not activated in AD suggesting the pathway is compromised in AD. Our future investigations are to determine what parts of the pathway are aberrant in disease progression and identify small molecule inhibitors to block chronic UPR pathway activation which is contributing to neuronal dysfunction and loss.

By assessing the interaction of these three convergent pathways in neurons responding to neurodegenerative stimuli such as oxidative damage, misfolded proteins, and inflammation, we hope to gain a greater understanding of the basic mechanisms underlying neuronal damage, dysfunction and loss in neurodegenerative diseases and identify drugable targets for treatment of AD, PD, and HIVE.

Selected Publications:

• Jordan K.L., Haas, A.R., Logan, T.J., and Hall D.J. Detailed analysis of the basic domain of the E2F1 transcription factor indicates that it is unique among bHLH proteins. 1994. Oncogene. 9,1177-1185.
• Logan T.J., Jordan K.L., and Hall D.J. Altered shape and cell cycle characteristics of fibroblasts expressing the E2F1 transcription factor.1994. Molecular Biology of the Cell. 5,667-678.
• Logan T.J., Jordan K.L., and Hall D.J. Constitutive expression of wild-type and mutant E2F1 alters G0 and S phase transit following serum stimulation. 1996. Biochemistry and Cell Biology. 74,21-28.
• Jordan, K.L., Evans, D.L., Steelman, S. and Hall, D.J.  Isolation of two novel cDNA's whose products associate with the amino-terminus of the E2F1 transcription factor. 1996. Biochemistry. 35(38):12320-12328.
• Logan, T.J., Jordan, K.L., Evans, D.E., and Hall, D.J. Altered cell shape is linked to increased p34cdc2 gene expression in fibroblasts expressing a mutant E2F-1 transcription factor. 1997. Journal of Cellular Biochemistry. 65:83-94.
• Jordan-Sciutto, K.L., Logan, T.J., Norton, P., Derfoul, A., Dodge, G.R., and Hall, DJ. Reduction in fibronectin expression and alteration in cell morphology are coincident in NIH3T3 cells expressing a mutant E2F1 transcription factor. 1997. Experimental Cell Research. 236(2):527-36.
• Jordan-Sciutto, K.L. and Bowser, R. Alzheimer's disease and brain development: Common molecular pathways. 1998. Frontiers in Bioscience. 3:100-112.
• Jordan-Sciutto, K., Dragich, J., Walcott, D., and Bowser, R. The presence of FAC1 protein in Hirano bodies. 1998.  Neuropathology and Applied Neurobiology. 24:359-366.
• Jordan-Sciutto, K.L. and Hall, D.J. A mutant E2F-1 transcription factor that affects the phenotype of NIH3T3 fibroblasts inefficiently associates with CyclinA/cdk2. 1998. Biochemistry and Cell Biology. 76(1):37-44.
• Jordan-Sciutto, K.L., Dragich, J., and Bowser, R. DNA binding activity of the fetal Alz-50 clone1 (FAC1) protein is enhanced by phosphorylation. 1999. Biochemical and Biophysical Research Communications. 260:785-789.
• Jordan-Sciutto, K.L., Dragich, J., Rhodes, J. L., and Bowser, R.  Fetal Alz-50 clone 1, a novel zinc-finger protein, binds a specific DNA sequence and acts as a transcriptional regulator. 1999.  Journal of Biological Chemistry. 274(49):35262-35268.
• Jordan-Sciutto, K.L., Morgan, K., and Bowser, R. Increased cyclin G1 immunoreactivity during Alzheimer's disease. 1999. Journal of Alzheimer's Disease. 1:409-417.
• Jordan-Sciutto, K.L., Dragich, J., Caltagarone, J, and Bowser, R. Fetal Alz-50 clone 1 (FAC1) protein represses transcriptional activation by the myc associated zinc finger protein (ZF87/MAZ).  2000. Biochemistry. 39:3206-3215.
• Jordan-Sciutto, K.L., Wang, G., Murphy-Corb, M., and Wiley, C.  Induction of cell cycle regulators in simian immunodeficiency virus encephalitis. 2000. American Journal of Pathology. 157:497-507.
• Jordan-Sciutto, K.L., Murray, B., Wiley, C.A., and Achim, C.L. Response of Cell Cycle Proteins to Neurotrophic Factor and Chemokine Stimulation in Human Neuroglia. 2001. Experimental Neurology. 167:205-214.
• Jordan-Sciutto, K.L., Rhodes, J, and Bowser, R. Altered subcellular distribution of transcriptional regulators in response to Ab peptide and during Alzheimer's disease. 2001. Mechanisms of Aging and Development, 123:11-20.
• Jordan-Sciutto, K.L., Wang, G., Murphy-Corb, M., and Wiley, CA.  Induction of cell cycle protein expression and activity in lentiviral associated encephalitis. 2002. Journal of Neuroscience. 22(6): 2185-2195.
• Jordan-Sciutto, K.L., Malaiyandi, L.M, and Bowser, R. Altered distribution of cell cycle transcriptional regulators during Alzheimer's disease. 2002. Journal of Neuropathology and Experimental Neurology. 61(4):358-367.
• Strachan, G.D., Jordan-Sciutto, K.L., Rallapalli, R.,Tuan, R.S., and Hall, D.J. The E2F-1 transcription factor is negatively regulated by its interaction with the MDMX Protein. 2003. Journal of Cellular Biochemistry. 88:557-568.
• Jordan-Sciutto, K.L., Dorsey, R., Chalovich, E.M., Hammond, R. and Achim, C.A. Cell cycle protein expression patterns in Parkinson's disease. 2003. Journal of Neuropathology and Experimental Neurology. 62:68-74.
• Rhodes, J., Lutka, F.A., Jordan-Sciutto, K.L., and Bowser, R.  Altered expression and distribution of FAC1 during NGF induced neurite outgrowth of PC12 cells. 2003. Neuroreport. 14(3):449-52.
• Smith, P.D., Crocker, S.J., Jackson-Lewis, V., Jordan-Sciutto, K.L., Hayley, S., Mount M.P., O'Hare, M.J., Callaghan, S, Slack, R.S., Przedborski, S., Anisman, H. and Park, D.S. Cyclin-dependent Kinase5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. 2003. Proceeding of the National Academy of Science, USA.  100:13650-13655.
• Strachan, G.D., Morgan, K.L., Caltagarone, J., Gittis, A, Bowser, R and Jordan-Sciutto, K.L. Fetal Alz-50 Clone 1 (FAC1) Interacts with the Human Ortholog of the Kelch-like Ech Associated Protein (Keap1). 2004. Biochemistry. 43(38):12113-12122.
• Strachan, G.D., Kopp, A.S, Koike, M.A., Morgan, K.L., and Jordan-Sciutto, K.L. Chemokine- and neurotrophic factor-induced changes in E2F1 localization and phosphorylation of the retinoblastoma susceptibility gene product (pRb) occur by distinct mechanisms in murine cortical cultures. 2005. Experimental Neurology, 193(2):455-468.
• Thangam, E.B., Venkatesha, R.T., Zaidi, A.K., Jordan-Sciutto, K.L., Amrani, Y, Panettieri Jr, R.A, and Ali, H. Airway smooth muscle cells do not express receptors for complement components C3a and C5a but they enhance C3a-induced mediator release in mast cells. 2005.  FASEB Journal. 19(7):798-800.
• Morgan, K.L., Chalovich, E.M., Otis, L.L., Wiley, C.A., and Jordan-Sciutto, K.L. E2F4 expression patterns in SIV encephalitis. 2005. Neuroscience Letters. 382(3):259-264.
• Li, Y., Decker, S., Yuan, Z., Chen, E, DenBesten, P.K., Aragon, M.A., Jordan-Sciutto, K., Abrams, W.R., Huh, J., McDonald, C., and Gibson, C.W.  Effects of Sodium Fluoride on the Cytoskeleton of Murine Dental Cells. 2005. Archives in Oral Biology. 50(8):681-688. 
• Strachan, G.D., Ostrow, L.A., and Jordan-Sciutto, K.L.  Expression of the Fetal Alz-50 Clone 1 protein (FAC1) induces apoptotic cell death. 2005. Biochemical and Biophysical Research Communications.  336(2):490-5.
• Strachan, G.D., Koike, M.A., Siman, R., Hall, D.J., and Jordan-Sciutto, K.L. E2F1 induces cell death, calpain activation, and MDMX degradation in a transcription independent manner implicating a novel role for E2F1 in neuronal loss in SIV encephalitis. 2005. Journal of Cellular Biochemistry. 96(4):728-40.
• Chalovich, E.M., Koike, M.A., Aras, M.A., Murphey-Corb, M., Wiley, C.A., and Jordan-Sciutto, K.L.  Pocket proteins, p107 and p130, exhibit increased expression in SIV infected macrophages in SIV encephalitis. 2005. Neuropathology. 25(4):315-25.
• O'Donnell, L.A., Agrawal, A., Jordan-Sciutto, K. L., Dichter, M.A., Lynch, D.R., and Kolson, D.L. Human immunodeficiency virus (HIV)-induced neurotoxicity: Roles for NMDA receptor subtypes. 2006. Journal of Neuroscience. 26(3):981-90.
• Boesze-Battaglia, K.*, Besack, D., McKay, T., Zekavat, A., Otis, L., Jordan-Sciutto, K.L. and Shenker, B.J. Cholesterol-rich Membrane Microdomains Mediate Cell Cycle Arrest Induced by Actinobacillus actinomycetemcomitans Cytolethal Distending Toxin. 2006. Cellular Microbiology. 8(5):823-36.
• Wang, Y., Xie, W., He, Y., Wang, M., Yang, Y., Zhang, Y., Yin, D., Jordan-Sciutto, K.L., Han, J., Wang, Y.* Role of CDK5 in Neuroprotection from Serum Deprivation by µ-Opioid Receptor Agonist. 2006. Experimental Neurology. 202(2):313-23
• Ramsey, C.P. &, Glass, C.A. & , Montgomery, M.B., Lindl, K.A., Ritson, G.P., Chia, L.A., Hamilton, R.L., Chu, C.T., and Jordan-Sciutto, K.L.* Expression of Nrf2 in Neurodegenerative Diseases. 2007. Journal of Neuropathology and Experimental Neurology . 66(1):75-85.
• Markowitz, A.J.B., White, M.B., Kolson, D.L., and Jordan-Sciutto, K.L. Cellular interplay between neurons and glia: toward a comprehensive mechanism for excitotoxic neuronal loss in neurodegeneration. 2007. Cell Science Reviews. 4: No. 1. http://www.cellscience.com/journal/journalindex.asp
• Lindl, K.A., Akay, C., Wang, Y., White, M.G., and Jordan-Sciutto, K.L.* Expression of the Endoplasmic Reticulum Stress Response marker, BiP in the Central Nervous System of Human Immunodeficiency Virus Positive Individuals. 2007. Neuropathology and Applied Neurobiology. In Press.
• Wang, Y., White, M.G., Akay, C., Chodroff, R.A., Robinson, J., Lindl, K.A., Dichter, M.A., Qian, Y., Mao, Z., Kolson, D.L., and Jordan-Sciutto, K.L.* Activation of cyclin dependent kinase 5 by calpains contributes to human immunodeficiency virus-induced neurotoxicity. Journal of Neurochemistry. In Press.
• Charleen T. Chu, Edward Plowey, Ying Wang, Vivek Patel, and Kelly L. Jordan-Sciutto. Location, Location, Location: Altered transcription factor trafficiking in neurodegeneration. Journal of Neuropathology and Experimental Neurology. In Press.

Mailing Address:
Robert Schattner Center
University of Pennsylvania
School of Dental Medicine
Rm 312 Levy Building
240 South 40th Street
Philadelphia, PA 19104-6030