About
Title: A Transdisciplinary Approach to Investigating Metabolic Dysregulation in Obese
Parent and Child Dyads and Risk of Colorectal Cancer
Institution: University of South Carolina at Columbia
Contact PI: James Hébert, ScD
Other PIs: Lorne Hofseth, PhD; Angela Murphy, PhD
NCI Program Director: Sharon Ross, PhD, MPH
NCI Project Scientist: Anil Wali, PhD
Institution: University of South Carolina at Columbia
Contact PI: James Hébert, ScD
Other PIs: Lorne Hofseth, PhD; Angela Murphy, PhD
NCI Program Director: Sharon Ross, PhD, MPH
NCI Project Scientist: Anil Wali, PhD
Read more about the project on the NIH website.
Abstract
This U01 project leverages our expertise in the epidemiology of colorectal cancer
(CRC); disparities; obesity; metabolic dysregulation, an important manifestation of
inflammation; the microbiome; animal CRC models; and lifestyle intervention trials
to address the growing problem of Early-Onset CRC (EOCRC) (i.e., <50 years). Adiposity
and diet drive metabolic dysregulation. So, understanding the interaction between
diet and adiposity are key to understanding the genesis of EOCRC – and an array of
other obesity-related cancers).
This project will address the absence of critical clinical trials and mechanistic
studies involving lifestyle interventions for EOCRC. We intend to address this gap;
and have the transdisciplinary team representing complementary backgrounds to do so.
We focus on dietary modulation of gut microbes to reduce metaflammation and subsequent
metabolic dysfunction in obesity, with a goal of preventing EOCRC. We will perform
1) an anti- inflammatory dietary intervention trial in dyads of adults and children
at elevated risk for CRC. We also will conduct a complementary mechanistic animal
study that builds on and leverages our expertise in mechanistic studies on obesity
and CRC.
This work is supported by infrastructure that we have built over the past decades
in two key centers at the University of South Carolina (UofSC): (1) Center for Colon
Cancer Research (CCCR, 2002 - present – which specializes in mouse models of CRC);
and (2) the Cancer Prevention and Control Program (CPCP, 2000 - present – which specializes
in the epidemiology of cancer and lifestyle intervention trials for cancer, with a
focus on cancer disparities.
The two projects that comprise the proposed grant address two Specific Aims that are
represented by the human study and laboratory animal experiment: i.e. ,1: To establish
the metabolic protective effects of an anti-inflammatory diet in obese, high-risk
African- American (AA) and European-American (EA) adults and children in reducing
inflammation as indicated by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR),
IGF-1, Tumor Necrosis Factor alpha (TNFα), Interleukin 6 (IL-6), and C-Reactive Protein
(CRP), and a creating more favorable microbiome signature; 2: To establish gut microbes
as mediators between anti-inflammatory dietary input and reversal of metabolic dysfunction
and associated CRC risk. This complements the human study by carrying out pre-clinical
murine model studies with similar inputs (diet), intermediate endpoints (inflammation,
microbiome), and outcomes (CRC-related). We hypothesize that an anti-inflammatory
dietary intervention will reduce metabolic dysfunction and metainflammation through
regulatory effects on gut microbiota.
Results from this work will address the role of metabolic dysregulation in relation
to factors that are known to be important in carcinogenesis, that therefore could
have profound effects on EOCRC, have implications for other obesity-related cancers,
and have great promise for moving the field forward by addressing mechanisms that
drive large health-related disparities that consistently disfavor African Americans.