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Laura Steel

Laura Steel, PhD

Associate Professor


Department: Microbiology & Immunology

Education

  • PhD - Cornell University (1977)

Laura Steel, PhD, is an associate professor in the Department of Microbiology & Immunology at Drexel University College of Medicine.

Research Interests

Development of RNAi-based therapies for hepatitis B virus (HBV) and HIV-1

Research

The research in our laboratory is aimed at understanding the role of microRNAs (miRNAs) in shaping the outcome of viral infections. Our interests include the utilization of miRNAs as antiviral therapeutics as well as an exploration of the role of miRNAs in the interplay between viruses and their host cells in the course of an infection.

Our efforts originally focused on developing RNA silencing-based therapies for hepatitis B virus (HBV). Approximately 400 million people are chronically infected with HBV and therefore are 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 a resistant virus, or can be difficult for the patient to tolerate. Our laboratory has developed vectors that allow the simultaneous expression of multiple interfering RNAs that target viral transcripts. This is a strategy that should maximize efficacy against a broad range of viral genotypes while minimizing the potential for the emergence of escape mutants. We have developed a series of vectors to express miRNA-formatted interfering RNAs that target HBV transcripts, including both viral RNA replicative intermediates and mRNAs that encode viral proteins. Our vectors have shown potent silencing of HBV targets in cell culture and animal models of HBV infection. We have applied similar principles of design in the development of silencing vectors that target HIV-1 and are inducible in HIV-1 infected cells.

Our laboratory has also investigated the interplay between HIV-1 and the cellular RNA silencing pathway. In plants, fungi, and invertebrates, RNA interference is a significant component of the cellular antiviral defense system, and it is of interest to understand whether it has a similar function in mammalian cells. Interactions between HIV-1 and the RNA silencing pathway are suggested since some proteins involved in HIV-1 replication also have a role in the processing of miRNAs. For instance, the cellular protein TRBP enhances expression from TAR-containing viral transcripts, and it is also a necessary co-factor for Dicer activity in RNA silencing. However, we have found no evidence of competition for TRBP activity between silencing and viral replicative functions. Instead TRBP appears to promote viral replication primarily through its activity as an inhibitor of the dsRNA-dependent kinase, PKR. Further evidence from our lab suggests that RNA silencing does not play a significant role in the direct suppression of HIV-1 replication, although there is clearly a complex interaction between miRNA and gene expression changes that are induced in infected cells.

Currently, we are undertaking the use of novel techniques such as HITS-CLIP and PAR-CLIP to define the miRNA targeted transcriptome in hepatocytes to understand alterations that are induced by infection with HBV and that contribute to the progression of liver disease in chronically infected individuals. Although HBV is not a cytopathic virus, long-term infection leads to a greatly increased risk of hepatocellular carcinoma. We are interested in understanding how chronic infection changes the homeostatic balance in hepatocytes, leaving them susceptible to insults that eventually result in end-stage liver disease.

Patent Application

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

In the Media

Publications

Books and Book Chapters

Gene Transfer Methods: Introducing DNA into Living Cells and Organisms
Norton PA and LF Steel (eds.)
Eaton Publishing, Natick: 2000

"Polycistronic expression of interfering RNAs from RNA polymerase III promoters"
Steel LF and Sanghvi VR
In Functional Genomics, 2nd editon; Eds. M. Kaufmann and C. Klinger.  Methods in Molec. Biol.,  815: 347-359, 2011

Selected Publications (See all Laura Steel's publications in PubMed.)

"RNA silencing as a cellular defense against HIV-1 infection: progress and issues"
Sanghvi VR and LF Steel
FASEB J., 26: 3937-3945, Epub ahead of print Jul 2, 2012.

"The cellular TAR RNA binding protein, TRBP, promotes HIV-1 replication primarily by inhibiting the activation of double-stranded RNA-dependent kinase PKR"
Sanghvi VR and LF Steel
J.Virol. 85: 12614-12621, 2011.

"A re-examination of global suppression of RNA interference by HIV-1"
Sanghvi VR and Steel LF
PLoS One, 6(2): e17246, 2011

"Expression of interfering RNAs from an HIV-1 Tat-inducible chimeric promoter"
Sanghvi VR and Steel LF
Virus Research, 155: 106-111, 2010

"Multiple functional miRNAs can be produced from a single RNA polymerase III promoter"
Snyder LL, Ahmed I, and Steel LF
Nucleic Acids Research, 37: e127, 2009

"Vector design for liver-specific expression of multiple interfering RNAs that target hepatitis B virus transcripts"
Snyder LL, Esser JM, Pachuk CJ, and Steel LF
Antiviral Research, 80(1): 36-44, 2008

"GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma"
Marrero JA, Romano PR, Nikolaeva O, Steel L, Mehta A, Fimmel CJ, Comunale MA, D'Amelio A, Lok AS and Block TM
Journal of Hepatology, 43:1007-1012, 2005

"SELDI-TOF-MS profiling of serum for detection of the progression of cirrhotic hepatitis C disease to hepatocellular carcinoma"
Schwegler EE, Cazares L, Steel LF, Adam BA, Johnson DA, Semmes OJ, Block T, Marrero JA, and Drake RR
Journal of Hepatology, 41:634-642, 2005

"Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and people"
Block TM, Comunale MA, Lowman M, Steel LF, Romano PR, Fimmel C, Tennant BC, London WT, Evans AA, Blumberg BS, Dwek RA, Mattu TS, and Mehta AS
Proceedings from the National Academy of Sciences, 102:779-784, 2004

"Methods of comparative proteomic profiling for disease diagnosis"
Steel LF, Haab BB, and Hanash SM
Journal of Chromatography B, 815:275-284, 2004

"Comparative proteomic analysis of de-N-glycosylated serum from hepatitis B carriers reveals polypeptides that correlate with disease status"
Comunale MA, Mattu TS, Lowman M, Evans AA, London WT, Semmes, OJ, Ward M, Drake R, Romano PR, Steel LF, Block TM, and Mehta A
Proteomics, 4:826-838, 2004

"Efficient and specific removal of albumin from human serum samples"
Steel LF, Trotter MG, Nakajima, PB, Mattu, TS, Gonye G, and Block TM
Molecular & Cellular Proteomics, 2.4: 262-270, 2003

"A strategy for the comparative analysis of serum proteomes for the discovery of biomarkers for hepatocellular carcinoma"
Steel LF, Shumpert D, Trotter M, Seeholzer SH, Evans AA, London WT, Dwek R, and Block TM
Proteomics, 3:601-609, 2003

"A proteomic approach for the discovery of early detection markers of hepatocellular carcinoma"
Steel LF, Mattu TS, Mehta A, Hebestreit H, Dwek R, Evans A, London WT, and Block T
Disease Markers, 17:179-189, 2001

"Elements in the murine c-mos messenger RNA 5'-untranslated region repress translation of downstream coding sequences"
Steel LF, Telly DL, Leonard J, Rice BA, and Sawicki JA
Cell Growth & Differentiation, 7:1415-1424, 1996


Contact Information


Research Office

Department of Microbiology & Immunology
245 N. 15th Street
Philadelphia, PA 19102
Phone: 215.762.8621
Fax: 215.762.1479