Toll- Like Receptor-Complex in Intestinal Epithelial Cells

Project: Research project

Project Details

Description

Program Director/Principal Investigator (Last, First, Middle): Abreu. Maria T. 3 R56 AI052266-07S1
ABSTRACT
During the last project period, a great deal has been learned about toll-like receptor
(TLR) signaling. The work we have performed on the present project entitled "Toll-like
receptor complex in intestinal epithelial cells" has helped to define the role of TLR
signaling in the intestinal epithelium. Based on our own research and recent work by
others, we wish to test the hypothesis that TLR4 links innate immune signaling to APC-
dependent sporadic colon cancer. Specifically, we plan to focus on this rather new
pathway in the colonic epithelial cell and the intestinal macrophage because of the close
interaction between these two important cell types. The work proposed is a direct
extension of our work in the previous period which dealt with the gut innate immune
system, but which now connects these pathways to understand mechanisms of
colorectal neoplasia. A great deal of research has elucidated the molecular pathways
that result in colon cancer. Mutations in the adenomatous polyposis coli (APC) gene
andlor the Wnt signaling pathway are found in 85% of sporadic colon cancers. Part of the
mechanism by which APC mutations result in colon cancer is through induction of
COX-2 and activation of epidermal growth factor receptor (EGFR) signaling. We have
shown that both of these pathways are activated by TLR4 in intestinal epithelial cells
(lEC) 2. The APC pathway to cancer seems to be particularly relevant in the colon, as
distinct from other epithelia, but the reason why APC mutations disproportionately
culminate in colon cancer are unknown. Bacteria and TLR signaling have been
implicated in the development of colorectal cancer. In preliminary data, we show that
TLR4 is over-expressed in most sporadic colon cancers. These compelling findings force
us to understand how TLR4 participates in the development of sporadic colon cancer.
Based on our preliminary data, we hypothesize that TLR4 signaling supports the
development of APC-dependent colorectal cancers through several distinct
mechanisms. First, TLR4 may interact with APC to activate target genes such as COX-2.
Second, TLR4 is both a target of EGFR signaling as well as capable of activating EGFR
resulting in dysregulated proliferation. Finally, TLR4 expression by the epithelium leads
to the recruitment of tumor-associated macrophages, which are required to promote
tumor growth. Studying TLR4 provides a framework to understand how the innate
immune system in the gut may inadvertently promote the development of cancer as an
extension of its normal role in repair. These studies offer an additional avenue by which
to prevent colon cancer in susceptible hosts and treat patients with colon cancer. This
proposal is a natural extension of the work performed during the four and a half years of
our grant.
StatusFinished
Effective start/end date9/5/085/31/11

Funding

  • National Institute of Allergy and Infectious Diseases: $382,500.00
  • National Institute of Allergy and Infectious Diseases: $382,500.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.