Role of Alcohol and Circadian Disruption in Inflammation and Colon Cancer

Project: Research project

Project Details

Description

Alcohol intake contributes to serious health issues including colorectal cancer (CRC). However, the exact
mechanism(s) of ethanol-associated carcinogenesis, have remained obscure, as ethanol itself is not a
carcinogen. Circadian disruption is a common feature among alcoholics. Epidemiological studies have linked
non-traditional work schedules (e.g., shift work) with increased risks of cancer. The overall goal of this
Project is to establish that alcohol consumption contributes to serious risk of colon cancer when combined
with desynchronization of circadian rhythms and to reveal the underiying cellular immunologic mechanisms.
We have evidence for inflammation driving polyposis, for mast cells orchestrating inflammation, and for
regulation of mast cells and inflammation by Tregs. Alcohol fed mice whose circadian rhythms were
disrupted by chronic shifting of the light/dark cycle developed overt intestinal and colonic inflammation,
resulting in expanded mitotic proliferation zone and crypt elongation. We hypothesize that alcohol and
desynchronization of circadian rhythms act synergistically to increase inflammation and susceptibility to
colon cancer. Here we propose to test this hypothesis in a novel mouse model: mice that spontaneously
develop benign polyps in their colon and distal ileum. In Aim 1 we will establish the extent to which alcohol
synergizes with environmental desynchronization of central and peripheral circadian rhythms through
light/dark shift and food restriction to cause inflammation, exacerbate polyposis, and promote CRC. The role
of mast cells and Tregs in this process will be addressed by genetic and pharmacologic interventions. In Aim
2, we will use a genetic approach to establish that the circadian disruption of immune cells plays a
considerable role in pathophysiology of alcohol induced colon cancer. We will generate through bone
marrow chimerism mice that are predisposed to polyposis and also express a dominant negative Clock
mutant in the immune compartment. The proposed studies are significantly relevant as a potential model for
humans engaged in lifestyle-related disruption of proper circadian organization.Our findings will provde new
paradigms for cancer prevention and targeted therapy.
RELEVANCE (See instructions):
Alcohol promotes cancer develoment/progression in a subset of individuals; however, it is not clear what
factor(s) confer susceptibility. Identification of disrupted circadian rhythms as a predisposing factor for
cancer devebpment/progression may.lead to new prevention strateges or treatment strategies (i.e.,
chronobiological therapy and/or pro- or pre-biotics) for alcohol-induced cancer.
StatusFinished
Effective start/end date2/5/141/31/19

Funding

  • National Institutes of Health: $24,674.00
  • National Institutes of Health: $364,567.00
  • National Institutes of Health: $50,000.00
  • National Institutes of Health: $340,778.00
  • National Institutes of Health: $460,068.00

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