My long-term career goals are to become an independent investigator studying the role of cell death in diseases of the Gl tract. My previous research experience in cell and molecular biology related to cell death included my doctoral dissertation on the role of mitochondrial mutations in age-related disease. I have identified a highly successful mentor in the area of cell death in hepatobiliary diseases, including cancer. The lab is in the conducive environment of the Center for Basic Research in Digestive Diseases, at Mayo Clinic, Rochester. This proposal outlines a testable hypothesis to define the role of microRNAs as regulators of apoptosis in cholangiocarcinoma, a malignant neoplasm that occurs in the presence of chronic inflammation of bile ducts. The current proposal will allow the candidate to change research directions by providing advanced training in hepatobiliary disease and cancer biology as it relates to cell death. Short-term career goals include advanced training in cancer biology and Gl-related translational research. These immediate goals will be achieved by the career development plan, including research, communication skills, and mentoring training. The research plan stems from our previous observations that the antiapoptotic protein Mcl-1 is over-expressed in human cholangiocarcinoma and is a key regulator of cell death. One potential mechanism of Mcl-1 regulation is through microRNAs, short RNAs that act as sequence-specific silencers of protein expression. Our preliminary data shows that Mcl-1 expression is a predicted target of mir-29b, and antagonism of mir-29 increases Mcl-1 protein expression. Further, Mcl-1 is over-expressed in cholangio- carcinoma cells while mir-29b expression is decreased. Finally, blocking mir-29 protects cholangiocytes from cell death. These extensive and original observations support the OVERALL HYPOTHESIS of this grant that dysregulated expression of mir-29b results in over expression of Mcl-1, rendering this cancer apoptosis resistant. To address this hypothesis, we have established advanced cell culture models and molecular techniques to detect and alter expression of microRNAs. This project is relevant to public health as it addresses how bile duct cancers resist cell death, and as such resist chemotherapy. In addition, by testing a new pathway governing cancer cell death, we may define a novel set of targets to improve treatment of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK079875-05
Application #
8128448
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2007-09-20
Project End
2011-09-26
Budget Start
2011-09-01
Budget End
2011-09-26
Support Year
5
Fiscal Year
2011
Total Cost
$132,268
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Razumilava, Nataliya; Bronk, Steve F; Smoot, Rory L et al. (2012) miR-25 targets TNF-related apoptosis inducing ligand (TRAIL) death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma. Hepatology 55:465-75
Guicciardi, Maria Eugenia; Mott, Justin L; Bronk, Steven F et al. (2011) Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Exp Cell Res 317:107-16
Cazanave, Sophie C; Mott, Justin L; Bronk, Steven F et al. (2011) Death receptor 5 signaling promotes hepatocyte lipoapoptosis. J Biol Chem 286:39336-48
Kurita, Satoshi; Mott, Justin L; Cazanave, Sophie C et al. (2011) Hedgehog inhibition promotes a switch from Type II to Type I cell death receptor signaling in cancer cells. PLoS One 6:e18330
Cazanave, Sophie C; Mott, Justin L; Elmi, Nafisa A et al. (2011) A role for miR-296 in the regulation of lipoapoptosis by targeting PUMA. J Lipid Res 52:1517-25
Kurita, S; Mott, J L; Almada, L L et al. (2010) GLI3-dependent repression of DR4 mediates hedgehog antagonism of TRAIL-induced apoptosis. Oncogene 29:4848-58
Mott, Justin L; Kurita, Satoshi; Cazanave, Sophie C et al. (2010) Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, hedgehog, and NF-kappaB. J Cell Biochem 110:1155-64
Sosa Seda, Ivette M; Mott, Justin L; Akazawa, Yuko et al. (2010) Noxa mediates hepatic stellate cell apoptosis by proteasome inhibition. Hepatol Res 40:701-10
Cazanave, Sophie C; Elmi, Nafisa A; Akazawa, Yuko et al. (2010) CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am J Physiol Gastrointest Liver Physiol 299:G236-43
Steele, Robert; Mott, Justin L; Ray, Ratna B (2010) MBP-1 upregulates miR-29b that represses Mcl-1, collagens, and matrix-metalloproteinase-2 in prostate cancer cells. Genes Cancer 1:381-387

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