(Applicant's Description) The overall goal of this Program Project Grant is to determine the molecular mechanisms involved in the chemoprevention of colorectal cancer by non- steroidal anti-inflammatory drugs (NSAIDs). In this regard, we will specifically test the hypothesis that the cyclooxygenase (COX) pathway and/or its eicosanoid products play a role in colorectal carcinogenesis. Colorectal cancer is the second leading cause of cancer related deaths in the United States. This year alone, approximately 55,000 Americans will die from this disease. Recent clinical research has revealed a 40-50% reduction in mortality from colorectal cancer in persons who take aspirin and other NSAIDs on a regular basis. Cyclooxygenase enzymes are known targets for NSAIDS. Two isoforms of cyclooxygenase have been characterized and they are referred to as Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) in this proposal. Previous work conducted by investigators involved in this program grant has demonstrated that there is a 2-50 fold increase in COX-2 expression in 85% of human colorectal adenocarcinomas and in 45-50% of adenomas. The goals of this program are to test the hypothesis that COX or its eicosanoid products play a role in colorectal carcinogenesis and to determine the molecular mechanisms by which NSAIDs prevent colorectal cancer. Here we provide an overview of the projects proposed to test this hypothesis and highlight how planned interactions among the investigators will aid significantly in the success of this program project. In addition, the role of COX-2 and prostaglandins in the pathogenesis of colorectal cancer is discussed, so as to provide a rationale for undertaking the projects that are proposed. There are four projects and three cores included in this revised Program Grant application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077839-05
Application #
6628148
Study Section
Subcommittee G - Education (NCI)
Program Officer
Umar, Asad
Project Start
1999-04-07
Project End
2004-06-21
Budget Start
2003-02-01
Budget End
2004-06-21
Support Year
5
Fiscal Year
2003
Total Cost
$1,371,968
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hsu, Alice H; Lum, Michelle A; Shim, Kang-Sup et al. (2018) Crosstalk between PKC? and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium. Cell Rep 24:655-669
Liang, Xiaohuan; Daikoku, Takiko; Terakawa, Jumpei et al. (2018) The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten. PLoS Genet 14:e1007630
Wang, Dingzhi; DuBois, Raymond N (2018) Role of prostanoids in gastrointestinal cancer. J Clin Invest 128:2732-2742
Yuan, Jia; Deng, Wenbo; Cha, Jeeyeon et al. (2018) Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. Nat Commun 9:603
Cha, Jeeyeon; Dey, Sudhansu K (2017) Hunting for Fox(A2): Dual roles in female fertility. Proc Natl Acad Sci U S A 114:1226-1228
Wang, Dingzhi; Sun, Haiyan; Wei, Jie et al. (2017) CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer. Cancer Res 77:3655-3665
Mendelson, Karen; Pandey, Suveg; Hisano, Yu et al. (2017) The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine levels during zebrafish embryogenesis. Elife 6:
Yanagida, Keisuke; Hla, Timothy (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol 79:67-91
Sones, Jenny L; Cha, Jeeyeon; Woods, Ashley K et al. (2016) Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model. JCI Insight 1:
Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo et al. (2016) Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci U S A 113:E8079-E8088

Showing the most recent 10 out of 336 publications