Mechanisms of Carcinogenesis in Biliary Epithelia

Project: Research project

Project Details

Description

DESCRIPTION: (Adapted from the Investigator's Abstract): The overall objective
of this proposal is to define the cellular mechanisms responsible for the
malignant transformation of biliary epithelia. Since chronic inflammation of
the biliary tree predisposes to malignant transformation of cholangiocytes, the
long-term goal is to understand the mechanisms by which inflammatory mediators,
especially the inducible form of nitric oxide synthase (iNOS), contributes to
the development and progression of biliary tract cancers. The central
hypothesis is that NO derived from iNOS expression in cholangiocytes promotes
the development and progression of cholangiocarcinoma by inhibiting DNA repair
and cellular apoptosis via nitrosylation of critical proteins. Using molecular,
biochemical, and cell biological approaches, the PI will test this central
hypothesis in three specific aims. The first specific aim is to test the
hypothesis that NO directly inhibits base excision DNA repair proteins,
especially 8-oxodeoxyguanine glycosylase (hOGG1), resulting in potentiation of
DNA damage during oxidative stress. The second specific aim is to test the
hypothesis that NO inhibits the mitochondrial pathway of apoptosis by directly
nitrosylating procaspase 9 rendering cholangiocarcinoma cells resistant to
apoptosis-inducing treatments. The third specific aim is to test the hypothesis
that iNOS expression enhances tumor progression and metastases in
cholangiocarcinoma xenografts and promotes the development and progression of
cholangiocarcinoma in an animal model of this disease. Successful completion of
these proposed studies has the potential for development of new strategies to
prevent and treat malignant human liver diseases.
StatusFinished
Effective start/end date7/1/014/30/17

ASJC

  • Medicine(all)