Poison or remedy? The role of bile acids in colorectal cancer

Project: Research project

Call title (Call ID)

Faculty Development Competitive Research Grant Program 2019-2021

Project Description

Without question cancers represent the leading causes of morbidity and mortality worldwide. Among all, colorectal cancer (CRC) was the third most common sites of cancer diagnosed in 2012 and accounted for 10% of all cancer types. While the the risk of developing CRC has been associated with dietary habits, it has been also noted that the consumption of some specific dietary components such as calcium and vitamin D, may have protective effects. However, the underlying causes connected to critical biological processes are not well known.
In humans, at least 24 distinct bile acid (BA) types can be found in the colon from which secondary BAs such as lithocholic and deoxycholic acid, have been hypothesized to be carcinogenic. Interestingly, ursodeoxycholic acid, that has been identified as a potential chemoprotective compound against CRC. The small changes in BA chemical structure may contribute to the diverse biochemical and biological properties that they exert in cellular signaling, but there is a lack of data to fully understand this.
The current proposal aims to use the state of the art methods to :
1) analyze the properties i.e. toxicity, chemopreventive and immunogenic potential of large number of BAs and thus identify carcinogenic and chemopreventative BAs, their binding profile to farnesoid X, pregnane X and vitamin D receptors and identify their target genes involved in CRC.
2) analyze the BA composition of primary CRC cells from primary cells with different progression stages using metabolomics approaches to identify metabolomic biomarkers,
3) study the crosstalk of BA, vitamin D and detoxification pathways to advance the knowledge on the concurrent activation that may be beneficial for general detoxification of toxic compounds in the body and may be relevant for CRC development and progression.
The project contains four work packages (WP) 1-3 working towards the final goal of the project, which is to advance knowledge on BA signalling, its crosstalk and to use this knowledge to prevent or treat CRC. The interconnection of WP1-3 represents an applied strategy that start from in silico (WP1) continues with in vitro/ex vivo (WP2-3) investigations.
StatusActive
Effective start/end date1/31/1912/31/21

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Poisons
Bile Acids and Salts
Colorectal Neoplasms
Metabolomics
Vitamin D
Lithocholic Acid
Pregnanes
Biological Phenomena
Ursodeoxycholic Acid
Neoplasms
Calcitriol Receptors
Deoxycholic Acid
Feeding Behavior
Computer Simulation
Colon
Biomarkers
Calcium
Morbidity
Mortality
Genes

Keywords

  • cancer
  • transcription factors
  • nuclear receptors
  • nutrigenomics
  • drug-design
  • bile acids
  • lipid metabolism