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Penn Center for AIDS Research

Kelly L Jordan-Sciutto

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Chair, Department of Pathology, University of Pennsylvania, School of Dental Medicine

Contact information
240 S. 40th St
Rm 312-314 Levy Bldg
Philadelphia, PA 19104-6030
Office: 215 898-4196
Fax: 215 573-2050
Education:
B.S. (Cumulative Science)
Villanova University, 1991.
Ph.D. (Biochemistry & Molecular Biology)
Thomas Jefferson University, 1996.
Cert (Management Development Program)
Harvard University , 2014.
Cert ( iCARE Training on Crisis Management)
CAPS, University of Pennsylvania, 2019.
Cert (HHMI/BWF sponsored Science of Mentoring training and workshop)
University of Minnesota and Howard Hughes Medical Institute, 2019.
Cert (Unconscious Bias for Leaders - Impact on Decision-Making )
Perelman School of Medicine, 2020.
Post-Graduate Training
Post-doctoral Fellow, University of Pittsburgh Medical Center Division of Neuropathology, Department of Pathology, 1996-2000.
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Description of Research Expertise

Research Interests
-Assessing neuronal, astrocyte, and oligodendrocyte responses to neuroinflammatory stimuli (i.e. oxidative stress, chemokines/cytokines, excitotoxicity).
-Determining mechanisms of neuroprotection in neuroinflammatory insult.
-Molecular mechanisms underlying neuronal loss in neurodegenerative disorders (i.e. Alzheimer’s Disease, Parkinson’s disease, and HIV associated neurocognitive disorders). We are specifically interested in the role of cell cycle proteins, the endogenous antioxidant response and the endoplasmic reticulum stress response in neuronal dysfunction and damage.

Key words: Cell Cycle, Oxidative Stress Response, Antioxidant Response, Endoplasmic Reticulum Stress Response, PERK, Integrated Stress Response, Neurodegeneration, Transcription, Primary Culture, HIV associated Neurocognitive Disorder, HIV encephalitis, Alzheimer Disease, Parkinson disease, Retinoblastoma, E2F1, neuroinflammation.

Description of Research
Our laboratory investigates molecular mechanisms underlying neurodegenerative processes in the hopes of identifying common and unique players in determining neuronal dysfunction and survivall= among several neurodegenerative diseases driven by neuroinflammation. 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 ? 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.

Rotation Projects
1. Identification of the role of cdk5, E2F1 and Rb in models of neuroinflammation induced neuronal dysfunction and damage.

2. Investigation of the normal function of E2F1 in neuronal survival and function.

3. Analysis of pRb phosphorylation in response to neurotoxic vs neuroprotective stimuli.

4. Role of the unfolded protein response in neuronal loss in AD, PD, and HAND

5. Regulation of Nrf2 nuclear transport in neurons responding to oxidative stress, beta amyloid, neuroprotective factors, and neuroinflammation

6. Neuroinflammation in models of chronic pain

7. Role of BPTF in neurons

Lab personnel:
Çagla Akay Espinoza, M.D., Research Assistant Professor
Lindsay Festa, Ph.D., Post-doctoral Fellow
Bassam Zidane, D.D.S., D.Sc.D. Student
Naela Albloushi, D.D.S., D.Sc.D. Student
Claire Meurice, B.S., Graduate Student, Pharmacology Graduate Group
Claudia Lopez, B.S., Graduate Student, Neuroscience Graduate Group
Sarah Bond, B.S. Graduate Student, Biochemistry and Molecular Biology Graduate Group
Sean Ryan, B.S. ,Graduate Student, Cell and Molecular Biology Graduate Group, Genomics and Epigenetics program (co-mentored with Dr. Stewart Anderson)
Lindsay Roth, B.S., Graduate Student, Pharmacology Graduate Group (co-mentored with Dr. Judith Grinspan)
Shivesh Ghura, B.S., Graduate Student, Pharmacology Graduate Group

Selected Publications

Jackson Dan P, Ting Jenhao H, Pozniak Paul D, Meurice Claire, Schleidt Stephanie S, Dao Anh, Lee Amy H, Klinman Eva, Jordan-Sciutto Kelly L: Identification and characterization of two novel alternatively spliced E2F1 transcripts in the rat CNS. Molecular and cellular neurosciences 92: 1-11, Jun 2018.

Stern Anna L, Ghura Shivesh, Gannon Patrick J, Akay-Espinoza Cagla, Phan Jessica M, Yee Alan C, Vassar Robert, Gelman Benjamin B, Kolson Dennis L, Jordan-Sciutto Kelly L: BACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP-Dependent Mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 38(18): 4288-4300, May 2018.

Stern Anna L, Lee Rebecca N, Panvelker Nina, Li Jiean, Harowitz Jenna, Jordan-Sciutto Kelly L, Akay-Espinoza Cagla: Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 13(1): 64-76, Mar 2018.

Rom Slava, Zuluaga-Ramirez Viviana, Reichenbach Nancy L, Erickson Michelle A, Winfield Malika, Gajghate Sachin, Christofidou-Solomidou Melpo, Jordan-Sciutto Kelly L, Persidsky Yuri: Secoisolariciresinol diglucoside is a blood-brain barrier protective and anti-inflammatory agent: implications for neuroinflammation. Journal of neuroinflammation 15(1): 25, Jan 2018.

Erickson Michelle A, Jude Joseph, Zhao Hengjiang, Rhea Elizabeth M, Salameh Therese S, Jester William, Pu Shelley, Harowitz Jenna, Nguyen Ngan, Banks William A, Panettieri Reynold A, Jordan-Sciutto Kelly L: Erratum. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32(1): 535, 01 2018.

Gannon, P. J. Akay-Espinoza, C. Yee, A. C. Briand, L. A. Erickson, M. A. Gelman, B. B. Gao, Y. Haughey, N. J. Zink, M. C. Clements, J. E. Kim, N. S. Van De Walle, G. Jensen, B. K. Vassar, R. Pierce, R. C. Gill, A. J. Kolson, D. L. Diehl, J. A. Mankowski, J. L. Jordan-Sciutto, K. L.: HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via beta-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187(1): 91-109, JAN 2017.

Erickson, M. A. Jude, J. Zhao, H. Rhea, E. M. Salameh, T. S. Jester, W. Pu, S. Harrowitz, J. Nguyen, N. Banks, W. A. Panettieri, R. A., Jr. Jordan-Sciutto, K. L.: Serum amyloid A: an ozone-induced circulating factor with potentially important functions in the lung-brain axis. FASEB J 31(9): 3950-3965, 2017.

Erickson Michelle A, Jude Joseph, Zhao Hengjiang, Rhea Elizabeth M, Salameh Therese S, Jester William, Pu Shelley, Harrowitz Jenna, Nguyen Ngan, Banks William A, Panettieri Reynold A, Jordan-Sciutto Kelly L: Serum amyloid A: an ozone-induced circulating factor with potentially important functions in the lung-brain axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31(9): 3950-3965, 09 2017.

Monnerie, H. Romer, M. Jensen, B. K. Millar, J. S. Jordan-Sciutto, K. L. Kim, S. F. Grinspan, J. B.: Reduced sterol regulatory element-binding protein (SREBP) processing through site-1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro. J Neurochem 140(1): 53-67, 2017.

Stern, A. L. Lee, R. N. Panvelker, N. Li, J. Harowitz, J. Jordan-Sciutto, K. L. Akay-Espinoza, C.: Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response. J Neuroimmune Pharmacol 2017.

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Last updated: 10/13/2022
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