Project: Research project

Project Details


Short-chain fatty acid (SCFA) levels in the colon are greater than 200
mM, derived from fermentation of dietary fiber and other dietary
components. These SCFAs play critical roles in colonic cell physiology.
First, they are the principal energy source for colonic epithelial cells
via their metabolism by beta-oxidation in the colonic cell mitochondria.
Second, they are natural inducers of colonic cell differentiation both in
vivo, and of colonic carcinoma cell lines in vitro, and a differentiation
program that they initiate has a component pathway that results in
colonic cell apoptosis. Our previous work, and that of others, has
demonstrated a clear link among the metabolism of SCFAs, mitochondrial
gene expression and function, growth arrest and the entry of cells into
a pathway which results in differentiation and/or apoptosis. Moreover,
recent reports have provided compelling data for a direct role of
mitochondria in apoptosis in other systems. This application is to use
novel genetic mouse models, and genetic and biochemical manipulation in
culture, to define the pathways and mechanisms that link SCFAs, their
metabolism, mitochondrial function, and normal cellular development in
the colonic mucosa, and how perturbations of this pathway modulate
genetic and carcinogen initiated colon tumorigenesis.

There are 3 specific aims: 1) To utilize a genetic mouse model in which
there is a homozygous deletion of the nuclear gene for short-chain acyl
dehydrogenase (SCAD), which encodes the mitochondrial enzyme that
catalyzes the first step in mitochondrial beta oxidation of SCFAs, to
determine the role of SCFA metabolism in the effects of tributyrin, the
triglyceride of butyrate, on both chemically (AOM) and genetically (Apc)
initiated colon cancer, and on the intermediate end-points of aberrant
crypt focus formation, cell proliferation, and apoptosis; 2) based on our
data, to determine the role of mitochondrial function and interaction with
the waf1/cip1 gene in mechanisms of SCFA induced cell cycle arrest and
entry into a pathway of apoptosis in SW620 colonic epithelial cells in
culture; 3) to use waf1/cip1 null mice, and a mouse strain with a
conditional targeted inactivation of the nuclear gene for mitochondrial
cytochrome C, to test the following model: that SCFA inhibition of Apc
initiated gastrointestinal tumors is waf1/cip1 dependent; and that this
inhibition requires mitochondrial function, and not only metabolism of
Effective start/end date7/15/976/30/02


  • Cancer Research
  • Genetics
  • Molecular Biology
  • Oncology


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