The research in the Lemon lab focuses on the molecular pathogenesis of
hepatitis C. Dr. Lemon's research group is defining the structure of the
RNA segments that control the initiation of translation as well as
those recognized by the replicase complex
to initiate viral RNA synthesis. His group is, thus, dissecting
the mechanisms of hepatitis C virus RNA replication, and the process of
infectious particle assembly. Toward that end, they have developed
robust, cell-culture based hepatitis C virus
RNA and, more recently, virus replication systems, that allow
structure-function correlates to be studied using reverse molecular
genetics. Dr. Lemon is also interested in mechanisms of hepatocellular
injury in chronic hepatitis C. His research
group has developed transgenic mouse models of hepatitis
C-related liver injury, including hepatocellular carcinoma, and
constructed hepatoma-derived and other cell lines with conditional
expression of hepatitis C virus proteins. They are using
these cells and their infectious virus systems to study the
effects of hepatitis C virus protein expression on post-transcriptional
regulation of the retinoblastoma tumor suppressor protein and its effect
on host cell proliferation and chromosomal
stability. Dr. Lemon is also interested in the mechanisms by
which hepatitis C virus evades intrahepatic innate cellular immune
defenses. His group has shown that the NS3/4A serine protease directs
the cleavage of a key Toll-like receptor adaptor
protein, TRIF, resulting in an effective blockade of
dsRNA-induced activation of the transcription factors interferon
regulatory factor 3 (IRF-3) and NK-kB and their cognate gene targets.
The protease recognizes TRIF through a unique molecular
interaction that differs from its recognition of natural viral
polyprotein substrates, and also cleaves IPS-1, a recently recognized
signaling protein, thereby disrupting a second, TRIF-independent pathway
leading to interferon synthesis that
is initiated by and dependent upon the cellular DExH(D) RNA
helicase, RIG-I. The Lemon lab interacts closely with on- and off-campus
collaborators in studying interactions of hepatitis C virus with the
innate immune system investigating the role
of hepatitis C core protein expression in mitochondrial injury
in hepatitis C and in the construction and evaluation of inducible
transgenic mouse models in which cellular responses to hepatitis C virus
proteins can be studied.