Immunology Graduate Group
Randy Q. Cron, M.D., Ph.D.
Assistant Professor, Pediatrics
Address: Abramson Research Center, Rm. 1102B
Office Phone: (215) 590-1844
Lab Phone: (215) 590-3792
Fax: (215) 590-1258
Email: rqcron@mail.med.upenn.edu
Dr. Cron's Center for AIDS Research page
Dr. Cron's Children's Hospital of Philadelphia page
Education:
Post-doctoral Fellow, Stanford University
Post-doctoral Fellow, University of Washington
M.D., UCLA
Ph.D., University of Chicago
Pre-doctoral Fellow, National Institutes of Health
B.S., University of California, Riverside
Research Interests
Transcriptional regulation of cytokine genes and HIV-1 in primary CD4 T lymphocytes
Research Techniques: Tissue culture, molecular cloning, primary (mouse and human) T cell transfection, transgene preparation, flow cytometry, DNA/RNA and protein analysis, nuclear run-on assays, chromatin immunoprecipitation, DNase I hypersensitive site mapping, luciferase reporter gene assays, HIV-1 infection and monitoring.
Research Summary
Our lab's research interests are focused on the role of transcription factors in human immunodeficiency virus type-1 (HIV-1) and cytokine gene transcription in normal human adult peripheral blood and neonatal CD4 T cells. We are studying the role of nuclear factor of activated T cells (NFAT), and c-Maf transcriptional activator proteins in HIV-1 gene expression, and related cytokine gene expression, in neonates and adults. Regulating the transcriptional machinery of host CD4 T cells may lead to alternative approaches in the therapy of HIV-1 infection.
One clear difference between naïve neonatal and adult CD4 T cells is their ability to express CD40-ligand (CD40L, CD154). This appears to be controlled at the level of transcription, and the lack of NFAT1 proteins in the neonate may contribute to this deficiency in CD40L expression. A large part of our research effort is devoted to understanding the transcriptional regulation of the CD40L gene, particularly as it relates to decreased expression in the neonate and to increased expression in patients with systemic lupus erythematosus (SLE). Understanding the transcriptional mechanisms, which contribute to increased and prolonged expression of CD40L on CD4 T cells from patients with SLE, could lead to novel approaches in the therapy of SLE.
The non-mammalian hormone, ecdysone, and its receptors can be used to generate conditional transgene expression. We have recently generated transgenic mice that conditionally express the transcription factor, nuclear factor of activated T cells-1 (NFAT1), exclusively in T lymphocytes. The figure on the left is a Western blot using an anti-NFAT1 antibody to demonstrate the conditional expression of the NFAT1 transgene only in the presence of the ecdysone homolog, ponasterone A. The figure on the right shows that the human NFAT1 transgene is functionally active. Primary splenic lymhocytes from the NFAT1 conditional transgenic mouse were transiently transfected with NFAT-responsive reporter genes driven by the IL-2 promoter or by multiple NFAT binding sites. The T cells were then stimulated with phorbol ester and calcium ionophore in the presence or absence of ponasterone A. Luciferase reporter gene activity is reported along the ordiante and reveals dose-dependent increases in NFAT transcriptional activity with increasing concentrations of ponasterone A. These unique mice can now be used to analyze the role of NFAT1 in cytokine gene expression in primary T cells in vivo. |
Recent Publications
Cron, R.Q., Bort, S.J., Wang, Y., Brunvand, M.W., and Lewis, D.B. 1999. T cell priming enhances IL-4 gene expression by increasing NFAT. J. Immunol. 162:860-870.
Cron, R.Q., Bartz, S., Clausell, A., Bort, S.J., Klebanoff, S.J., and Lewis, D.B. 2000. NFAT1
enhances HIV-1 gene expression in primary human CD4 T cells. Clin. Immunol. 94:179-191.
Cron, R.Q., Zhou, B., Brunvand, M.W., and Lewis, D.B. 2001. Octamer proteins inhibit IL-4
gene transcription in normal human CD4 T cells. Genes Immunity 2:464-468.
Cron, R.Q. 2001. HIV-1, NFAT, and cyclosporin: immunosuppression for the immunosuppressed? DNA Cell Biol. 20:761-767.
Schubert, L.A., Cron, R.Q., Cleary, A.M., Brunner, M., Song, A., Lu, L.-S, Jullien, P., Krensky,
A.M., and Lewis, D.B. 2002. A T cell-specific enhancer of the human CD40 ligand gene. J. Biol. Chem. 277:7386-7395.
Zhou, B., Cron, R.Q., Wu, G., Genin, A., Wang, Z., Liu, S., Robson, P., and Baldwin, H.S.
2002. Regulation of the murine NFATc1 gene by NFATc2. J. Biol. Chem. 277:10704-10711.
Hamilton, B.J., Genin, A., Cron, R.Q., and Rigby, W.F.C. 2003. Delineation of a novel pathway that regulates CD154 (CD40 Ligand) expression. Mol. Cell. Biol. 23:510-525.
Cron, R.Q. 2003. CD154 transcriptional regulation in primary human CD4 T cells. Immunol. Res. 27:185-202.
Lab rotation projects for graduate students
1. Role of NFAT1 transcription factor in vivo using conditional transgenic expression.
2. Characterize novel CD40-ligand transcriptional regulatory elements in lupus.
3. Role of the c-maf transcription factor in HIV-1 gene transcription.
4. Analysis of Egr transcription factors in NFAT2 regulation.
Current Lab Personnel
Anna Genin, Research Specialist (M.D., Kiev Medical School, Ukraine)
Michael Brunner, Assistant Member, Stokes Institute (Ph.D., Pennsylvania State University)
Mingce Zhang, Post-doctoral fellow (Ph.D., Peking Union Medical College)
Shyamala Arunachalam, (Ph.D., University of Madras, Guindy Campus)