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Kenneth Alexander, M.D., Ph.D.
Human Papillomavirus Transcription Control,
DNA Replication, Innate Immune Responses and Antiviral Therapy
Research Summary
Human papillomaviruses (HPVs) cause anogenital dysplasias,
laryngeal papillomatosis, and common warts. Replication
of papillomaviruses requires a
differentiating epithelium. Within
HPV-infected epithelia, transcription
of viral proteins and replication of viral DNA are linked with the
process of
keratinocyte differentiation. Our research focuses on the biochemical
mechanisms that coordinate transcription and replication in human
papillomaviruses, and link these processes with keratinocyte
differentiation.
Papillomavirus transcription is controlled by the
virus-encoded E2 protein. E2 interacts
with a variety of host cell proteins, including components of the host
cell TFIID
complex. One project in the laboratory
seeks to discern what components of the TFIID complex interact with E2,
and how
these interactions affect transcription of both viral and host cell
genes.
In a second project, the interactions of the papillomavirus E1
protein (a DNA helicase/ATPase) with host cell proteins are being
investigated
to determine how viral DNA replication is controlled.
A third line of investigation is directed at the study of
chemically modified short interfering RNAs (siRNAs).
siRNAs in which the bridging phosphodiester linkages
have been replaced with a boranophosphate links show high gene
silencing
activity, and function as single strands. The
goals of this project are to make further
improvements in siRNA
activity and stability, to discern the biochemical bases for the potent
gene
silencing activity of boranophosphate siRNAs, and to use our
understanding of
modified siRNAs to develop highly active, highly stable siRNAs that
function as
antiviral microbicides.
A newly developing area of research in the laboratory is characterizing
the effects of HPV E6 on the signalling pathways that control innate
immunity.
Selected Papers
Alexander
KA and Phelps WC. (2000). Recent Advances
in Diagnosis and Treatment of
Human Papillomaviruses. Exp. Opin. Invest.
Drugs 9(8): 1753-1765
Hall
AHS and Alexander KA. (2003). RNA Interference of
HPV18 E6 and E7 Induces Senescence in HeLa Cells. J.
Virology 77(10): 6066-6069
Hall AHH, Wan J, Shaughnessy EE, Ramsay Shaw
B and Alexander KA. (2004). RNA interference using boranophosphate
siRNAs:
structure-activity relationships. Nucleic
Acids Research 32(20): 5991-6000
Alexander KA. (2005). Diagnosis and Treatment of Human
Papillomavirus Infections. Pediatr. Inf. Dis. J. 24(11): 1007-1008
Hall AHH, Wan J, Spesock A, Ramsay
Shaw B and Alexander KA. (2006). High
potency silencing by single-stranded boranophosphate siRNA. Nucleic
Acids Research 34(9): 2773-2781.
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