Aberrant kinase signaling in cholangiocarcinoma

Project: Research project

Project Details


DESCRIPTION (provided by applicant):
Although the association between chronic epithelial cell inflammation and
malignancy is well recognized, the pathophysiological mechanisms mediating the
enhanced potential for malignancy in inflammatory states remain unknown.
Chronic inflammation of the biliary tract such as in primary sclerosing
cholangitis or hepatolithiasis is characterized by alterations in the cytokine
milieu and predisposes to the development of neoplasia. With the support of a
K08 award (DK02678), we have demonstrated the role of the mitogen activated
protein kinase (MAPK) signaling pathways in the proliferation of human
cholangiocytes in response to inflammatory mediators. We have also identified
aberrant activation of the p38 MAPK signaling pathway in malignant, but not in
non-malignant, cholangiocytes. Furthermore, we have shown that p38 MAPK
signaling enhances anchorage independent growth, decreases expression of the
cell cycle regulator p21WAF1/CIP1, and modulates sensitivity to chemotherapy in
malignant cholangiocytes. Thus, our OVERALL HYPOTHESIS is that aberrant p38
MAPK signaling is a critical mediator of malignant transformation in biliary
epithelia. Our application has two Specific Aims. FIRST, we will assess the
role of p38 MAPK in phenotypic changes of malignant cells, namely invasion and
metastases, as well as in the modulation of angiogenesis. SECOND, we will
determine the role of p38 MAPK and p21WAF1/CIP1 on cell survival signaling
pathways and their relationship to chemosensitivity. We will use a variety of
biochemical and molecular approaches for in vitro studies on human normal and
malignant cholangiocyte cells in culture and an in vivo xenograft model of
cholangiocarcinoma. These studies will help us to elucidate the role of p38
MAPK signaling in the growth and spread of malignant cholangiocytes and provide
fundamental insights into the role of cell survival signaling pathways as
determinants of chemosensitivity. This information will ultimately contribute
to the development of specific therapies for biliary tract malignancies, as
well as interventions to treat or prevent neoplasia during chronic
StatusNot started


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