Laura Steel

Laura F. Steel

Assistant Professor, Microbiology and Immunology

Ph.D., 1977, Cornell University, Ithaca, New York

245 N. 15th Street
Mail Stop 1013A, Room 18313
Philadelphia, PA 19102 
Tel: 215-762-8621 
Fax: 215-762-1955 
Email: Laura.Steel@DrexelMed.edu

Research Staff: Lindsey Snyder
Graduate Students: Viraj Sanghvi

Keywords:

RNAi, hepatitis B virus, anti-viral therapy, cell stress, interferon response, miRNA, HIV-1.

Research Interests:

The research in our laboratory is aimed at helping to realize the tremendous therapeutic potential of RNA interference (RNAi). This new technology allows the specific knockdown of expression of targeted genes and is well-suited for anti-viral applications. Our efforts are currently focused on developing RNAi-based therapies for hepatitis B virus (HBV). Approximately 400 million people are chronically infected with HBV and therefore at high risk for end stage liver disease, such as cirrhosis and hepatocellular carcinoma. Current therapies are inadequate in that they are often ineffective, can lead to the emergence of resistant virus, or can be difficult for the patient to tolerate.

While several groups, including our own, have demonstrated the efficacy of RNAi in targeting viral gene products, many questions remain to be answered in order to use RNAi in a therapeutically safe and effective way. Our laboratory is exploring both vector design for high level expression of interfering RNAs in cells and methods of analysis of signaling pathways (e.g. interferon and cell stress pathways) that may be activated by that expression. We have developed a series of vectors to express interfering RNAs that target HBV transcripts, including both viral RNA replicative intermediates and mRNAs encoding viral proteins. Our vector design incorporates many features of endogenous microRNA (miRNA) gene organization that are proving useful for the development of reagents for RNAi. In particular, our vectors contain an RNA pol II driven gene cassette that leads to tissue specific expression and efficient processing of multiple interfering RNAs from a single transcript, without the co-expression of any protein product. This vector shows potent silencing of HBV targets in cell culture and animal models of HBV infection.

This work is carried out with the close cooperation and support of Nucleonics, Inc., a company whose mission is to develop, manufacture, and market therapeutic products based on RNAi technologies. In a second project, our laboratory is investigating the interplay between HIV-1 and the cellular RNAi pathway. In plants, RNAi is a significant component of the cellular anti-viral defense system, and it is increasingly apparent that it can have a similar function in mammalian cells. Interactions between HIV-1 and the RNAi pathway are evident in that several proteins involved in HIV-1 replication also have a role in the processing of miRNAs. For instance, the cellular protein TRBP is involved in HIV-1 Tat-TAR interactions and it is also a necessary co-factor for Dicer activity in the RNAi pathway. In addition, the HIV-1 transcriptional transactivator protein Tat has been identified as a suppressor of RNAi. We are exploring this interplay between HIV-1 and the endogenous RNAi pathway in infected cells. We are also characterizing the expression levels of several endogenous miRNAs that have the potential to target HIV-1 sequences. It will be of interest to discover whether there is a relationship between the ability of cells of the T-cell and monocyte/macrophage lineages to support HIV-1 replication and miRNA levels in these cells. These studies will help us to understand how interactions between the HIV-1 virus and miRNAs present in specific cell types can affect HIV-1 disease progression.

Selected Research Publications:

Steel, L.F. and A. Jacobson. Translational control of ribosomal protein synthesis during early Dictyostelium discoideum development. Mol Cell Biol 7: 965-972, 1987.
Steel, L.F., P.D. Farnum, and P. Kunapoli. Sequence and developmental regulation of the gene that encodes the Dictyostelium discoideum L3 ribosomal protein. Gene 162: 123-128, 1995.
Steel, L.F., D.L. Telly, J. Leonard, B.A. Rice, and J.A. Sawicki. Elements in the murine c-mos messenger RNA 5'-untranslated region repress translation of downstream coding sequences. Cell Growth & Differentiation 7: 1415-1424, 1996.
Steel, L.F., D.L. Telly, J. Leonard, B.A. Rice, and J.A. Sawicki. Elements in the murine c-mos messenger RNA 5'-untranslated region repress translation of downstream coding sequences. Cell Growth & Differentiation 7: 1415-1424, 1996.
Steel, L.F. Transformation of bacteria and purification of plasmid DNA, in Gene Transfer Methods: Introducing DNA into Living Cells and Organisms, eds. P. Norton and L. Steel, Eaton Publishing, 2000.
Steel, L.F., T.S. Mattu, D. Shumpert, M.A. Comunale, and T. Block. Analysis of human serum proteins by two-dimensional gel electrophoresis for the detection of biomarkers for hepatocellular carcimoma. Disease Markers 17: 26-27, 2001.
Steel, L.F., T.S. Mattu, A. Mehta, H. Hebestreit, R. Dwek, A. Evans, W.T. London, and T. Block. A proteomic approach for the discovery of early detection markers of hepatocellular carcinoma. Disease Markers 17: 179-189, 2001.
Steel, L.F., D. Shumpert, M. Trotter, S.H. Seeholzer, A.A. Evans, W.T. London, R. Dwek, and T.M. Block. A strategy for the comparative analysis of serum proteomes for the discovery of biomarkers for hepatocellular carcinoma. Proteomics 3: 601-609, 2003.
Steel, L.F., M.G. Trotter, P.B. Nakajima, T.S. Mattu, G. Gonye, T.M. and Block. Efficient and specific removal of albumin from human serum samples. Molec Cell Proteomics 2.4: 262-270, 2003.
Comunale, M.A., T.S. Mattu, M. Lowman, A.A. Evans, W.T. London, O.J. Semmes, M. Ward, R. Drake, P.R. Romano, L.F. Steel, T.M. Block, and A. Mehta. Comparative proteomic analysis of de-N-glycosylated serum from hepatitis B carriers reveals polypeptides that correlate with disease status. Proteomics 4: 826-838, 2004.
Steel, L.F., Haab, B.B., and Hanash, S.M. Methods of comparative proteomic profiling for disease diagnosis. J Chromatogr B 815, 275-284, 2004.
Norton, P.A., Conyers, B., Gong, Q., Steel, L.F., Block, T.M., and Mehta, A. Assays for glucosidase inhibitors with potential antiviral activities: Secreted alkaline phosphatase as a surrogate marker. J. Virol. Methods 124, 167-172, 2004.
Block, T.M., Comunale, M.A., Lowman, M., Steel, L.F., Romano, P.R., Fimmel, C., Tennant, B.C., London, W.T., Evans, A.A., Blumberg, B.S., Dwek, R.A., Mattu, T.S., Mehta, A.S. Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and people. Proc. Natl. Acad. Sci. 102, 779-784, 2004.
Schwegler, E. E., Cazares, L., Steel, L. F., Adam, B-A., Johnson, D. A., Semmes, O. J., Block, T., Marrero, J. A., and R. R. Drake. SELDI-TOF-MS profiling of serum for detection of the progression of cirrhotic hepatitis C disease to hepatocellular carcinoma. Hepatology, 41: 634-642, 2005.
Marrero, J. A., Romano, P. R., Nikolaeva, O., Steel, L., Mehta, A., Fimmel, C. J., Comunale, M. A., D’Amelio, A., Lok, A. S., and T. M. Block. GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma. J. Hepatol., 43: 1007-1012, 2005.

Patent Application: (PCT/US07/81103) MicroRNA-formatted multitarget interfering RNA vector constructs and methods of using the same.