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PPARs in intestinal and colonic tumorigenesis

Institution: Salk Institute for Biological Studies
Investigator(s): Yongxu Wang, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10FT-0033 Award: $74,952
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Colorectal cancer is the second leading cause of death from cancer in the United States. Recent studies have clearly shown that cigarette smoking, especially long term continuous smoking, can significantly increases the risk of colorectal cancer death in both men and women. The carcinogens in tobacco smoke are thought to damage genes in intestinal cells, which in turn lead to colorectal cancer. However, how exactly smoke does this is completely unknown; this is largely due to our insufficient knowledge of which genes are important for colorectal cancer. A group of proteins named PPARs have recently been implicated in this disease. When they bind to some small molecules called ligands, PPARs become activated and can perform their functions. These ligands include dietary fatty acids, anti-inflammatory drugs and anti-diabetic drugs. PPARs consist of three subtypes: PPAR, PPAR, and PPAR. Ligand-bound PPAR proteins have been found to enhance intestinal tumorigenesis in mice predisposed to intestinal tumors, while the same molecules inhibit the growth of human colon cancer cells. A possible role of PPAR in colorectal cancer has also been suggested by recent studies. In human colorectal cancer tissues, the level of PPAR increases. Moreover, PPARexpression is controlled by the protein named APC, a tumor suppressor that prevents colorectal cancer. However, definitive evidence concerning whether and how PPAR and PPAR participate in colorectal cancer is missing. In this proposal we will generate animal models that exhibit active forms of PPAR and PPAR in intestines to directly examine the in vivo function of PPARs in colorectal cancer. We will examine: (1) How PPAR or PPAR affects intestinal development(2) Whether the active form of PPAR or PPAR is sufficient to cause colorectal cancer; (3) How PPAR or PPARaffects cancer growth and/or progression in animal models of colorectal cancer; (4) What are the downstream genes regulated by PPARs in colorectal cancer. The results of this study will not only open a new direction to explore the mechanism of how smoke can cause colorectal cancer but also help to develop specific and effective ligands for treatment of this disease.

Peroxisome-proliferator-activated receptor delta activates fat mtabolism to prevent obesity.
Periodical: Cell Index Medicus:
Authors: Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM ART
Yr: 2003 Vol: 113 Nbr: Abs: Pg: 159-170