Medical Student Research Fellowship for Summer 2010

Mentor: James A. Bibb, PhD
Department: Psychiatry
Room number: NC5.410
Mail Code: 9070
Phone number: 214-648-4168
E-mail: james.bibb@utsouthwestern.edu
Project title: Aberrant Signaliing Links in Neurodegeneration and Cancer

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable): 0958-07-01-1

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) ANIMAL BASED

Brief Description of Project:
We derived a model of Alzheimer's disease using a bitransgenic system to inducibly overexpress p25, the truncated form of the Cdk5 cofactor p35 in the brain (Meyer, D.A., Richer, E., Benkovic, S.A. Janice W. Kansy, J.W., Hale, C., Moy, L. Kim, Y., James P. O'Callaghan, J.P. Tsai, L.-H., Greengard, P. Nairn, A.C.. Cowan, C.W. Miller, D.B., Antich, P., and Bibb, J.A. (2008) Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology, PNAS 105:18561-18566). P25 was labeled with GFP and induction of expression resulted in neurodegenerative pathology accompanied by lose of neurological function. Suprisingly the induction of GFP-p25 expression also occurred in interfollicular C-cells of the thyroid resulting in medullary thyroid carcinoma and 100% lethality by 24 weeks after induction (Castro-Rivera, E. Meyer, D.A., Richer, E. , Lagace1, D.C., Tsai, L-H. , Antich, P., Nwariaku, F.E., Richardson J.A., and Bibb, J.A., (2008) Medullary thyroid carcinoma induction by Cdk5 in a p25-overexpressing mouse, under revision for resubmission to Cancer Cell). We hypothesize that the underlying mechanisms involve activation of cell cycling factors including retinoblastoma protein and metastasis pathways involving tau and stathmin. Interestingly, these same pathways are invoked in AD. We will pursue the mechanisms by which Cdk5 causes MTC in human cell lines derived from MTC and use adenoviral vectors that target this novel Cdk5-Rb pathway as a potential therapy for MTC and neurodegeneration. This project will involve studies that span the fields of neuroscience, endocrinology, and oncology. It will include collaborations on histological studies with Drs. Jim Richardson in Pathology and Fiemu Nwariaku in Surgery and will involve substantial interactions including clinical exposure.

Previous Research Activities or Publications with Medical Students:

Adrian Brown, MD, UTSW Medical Student Research Fellow
Kansy, J.W., Katsovich, L., McIver, K., Pick, J. Leckman, J.F., Lombroso, P.J., Zabriskie, J.B., and J.A. Bibb, (2006) Identification of pyruvate kinase as an antigen associated with Tourette syndrome, J. Nueruoimmunology, 181:165-176.

Bogachan Sahin, M.D., Ph.D. Student, doctoral thesis
Sahin, B., Kansy, J.W., Nairn, A.C., Spychala, J., Ealich, S.E., Feinberg, A. A., Greene, R.W., and Bibb, J.A. (2004) Molecular characterization of mouse adenosine kinase. Eur. J. Biochem. 271:3547-55
Sahin, B., Hawasli, A.H., Greene, R.W. Molkentin, J.D., and Bibb, J.A. (2008), Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C. Eur. J. Pharmacol. 581:270-275.
Sahin, B, Galdi, S., Hendrick, J. Greene, R.W., Snyder, G.L., and J.A. Bibb (2007) Evaluation of neuronal phosphoproteins as mediators of striatal adenosine A2A receptor signaling and the actions of caffeine, Brain Research, 1129:1-14.
Sahin, B., H. Shu, Fernandez, J., Nairn, A.C., Molkentin, J.D., and J.A Bibb (2006). Dual phosphorylation of inhibitor-1 by PKC and Cdk5 regulates its conversion of an inhibitor of PP-1 by PKA in the striatum, J. Biol. Chem. 281:24322-24335.

Chan Nguyen, M.D., Ph.D. Student, doctoral thesis
Nguyen, C., Kansy, J. W., Fernandez, J., Gillardon, F., Allen, P.B., Hemmings, H.C., Jr., Nairn, A.C., and J.A. Bibb (2007) Regulation of protein phosphatase inhibitor-1 by Cyclin-dependent kinase 5. J. Biol. Chem. 282, 16511-16520.
Nguyen, C., Hosokawa, T., Ip, N.Y., Hisanga, S., and J.A. Bibb (2007) Differential regulation of the Cdk5-dependent phosphorylation sites of inhibitor-1 and DARPP-32 by depolarization. Jour. of Neurochem. 103:1582-1593.
Wei, F.-Y., Tomizawa, K., Ohshima, T., Asada, A., Nguyen, C., Bibb, J.A., Ishiguro, K., Saito, T., Kulkarni, A.B., Pant H.C., Mikoshiba, K., Matsui, H., and S. Hisanaga (2005) Control of Cdk5 activity by glutamatergic regulation of p35 stability. J. Neurochem. 93: 502-512.
Nguyen, C. and J.A. Bibb (2003) Cdk5 and the mystery of synaptic vesicle endocytosis. J. Cell Biology 163: 697-9.
Hawasli, A.H., Benavides, D.R., Nguyen, C., Kansy, J.W., Chambon, P, Greengard, P., Powell, C.M., Cooper, D.C., and Bibb, J.A. (2007) Cdk5 governs learning, memory and synaptic plasticity via control of NMDA receptor degradation. Nature Neuroscience 10:880-886.
Kansy, J., Daubner, S.C., Nishi, A., Soogaku, N., Lloyd, M.D., Nguyen, C., Lu, L., Haycock , J., Hope, B.T., Fitzpatrick, P.F., and Bibb, J.A. (2004) Identification of tyrosine hydroxylase as a physiological substrate of Cdk5. J. Neurochem. 91: 374-84.

Ammar Hawasli, M.D., Ph.D. Student, doctoral thesis
Hawasli, A.H., Benavides, D.R., Nguyen, C., Kansy, J.W., Hayashi, K., Chambon, P, Greengard, P., Powell, C.M., Cooper, D.C., and J.A. Bibb (2007) Cdk5 governs learning, memory and synaptic plasticity via control of NMDA receptor degradation. Nature Neuroscience, 10:880-886.
Hawasli A.H. and J.A. Bibb (2007) Alternative roles for Cdk5 in learning and synaptic plasticity. Jour. Biotechnol, 2:941-948.
Sahin, B., Hawasli, A.H., Greene, R.W. Molkentin, J.D., and Bibb, J.A. (2008), Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C. Eur.. Jour. Pharmacol. 581:270-275.
Benavides, D.R., Quinn, J.J., Zhong, P., Hawasli, A.H., DiLeone, R.J., Kansy, J.W., Olausson, P., Yan, Z., Taylor, J.R., and Bibb, J.A. (2007) Cdk5 controls cocaine reward, motivation, and striatal neuron excitability. J. Neurosci. 27:12967-12976.
Hawasli, A., Koovakkattu, D., Hayashi, K., Powell, C.M., Sinton, C., Bibb, J.A., and Cooper, D,.C. (2009) Cyclin-dependent kinase 5 attenuates hippocampal neuronal and behavioral excitability, to be submitted to PLOSOne.

David Benavides, M.D., Ph.D. Student, doctoral thesis
Benavides, D.R., Quinn, J.J., Zhong, P., Hawasli, A.H., DiLeone, R.J., Kansy, J.W., Olausson, P., Yan, Z., Taylor, J.R., and J.A. Bibb, (2007) Cdk5 modulates cocaine reward, motivation, and striatal neuron excitability. J. Neurosci. 27:1967-1976.
Lagace, D.C., Benavides, D.R., Kansy, J.W. Mapelli, M., Greengard,P., Bibb, J.A. Eisch, A.J. (2008) Cdk5 is essential for adult hippocampal neurogenesis, PNAS 105:18567-18571.
Hawasli, A.H., Benavides, D.R., Nguyen, C., Kansy, J.W., Chambon, P, Greengard, P., Powell, C.M., Cooper, D.C., and Bibb, J.A. (2007) Cdk5 governs learning, memory and synaptic plasticity via control of NMDA receptor degradation. Nature Neuroscience 10:880-886.