Research

Research

Obesity is rapidly on the rise and is associated with dysregulated metabolism, cardiovascular morbidity and increased rates of gastrointestinal malignancies. Moreover, obesity is driven by high-fat, high-cholesterol diets that are themselves serious risk factors for gastrointestinal cancers. The most rapidly-dividing cells in the body reside in the intestinal epithelium, which relies on progenitor cells like intestinal stem cells (ISCs) to sustain it. While dietary lipids are known to regulate ISCs, the mechanisms by which lipids affect intestinal proliferation are not well understood. Lipid biosynthesis is regulated by sterol regulatory element-binding proteins (SREBPs). Recent studies from the Engelking laboratory have demonstrated that SREBPs also have a critical role in sustaining growth of the intestinal epithelia. We found, surprisingly, that a deficiency all SREBPs results in a total collapse of the intestinal epithelia, while selective deficiency of SREBP-2, which selectively blocks cholesterol synthesis, results in marked intestinal overgrowth and increased numbers of intestinal progenitor cells. Our group’s central goal is to determine the molecular mechanisms by which SREBPs control intestinal epithelial proliferation. We hypothesize that SREBPs maintain homeostasis of intestinal epithelia by producing lipid metabolites that sustain proliferation of intestinal progenitors.

Current projects in the lab are to: (1) To determine how SREBPs drives the growth of intestinal epithelia & ISCs. (2) To identify the cellular compartment(s) where SREBPs mediate their effects on intestinal growth. (3) Using unbiased transcriptome and lipidome profiling, to identify the lipid metabolites and their biosynthetic enzymes that underlie the effects of SREBPs on the epithelium. (4) To determine how SREBP-2, and more broadly the enzymes and intermediates of the cholesterol biosynthetic pathway, control the growth of intestinal neoplasias such as colorectal cancer.

We specialize in using novel mouse models using Cre-loxP tools to modulate gene and marker expression in intestine in vivo, RNA-seq and lipidomics measurements, and intestinal organoids (human and rodent, tumor-derived and from normal intestines) for in vitro mechanistic experiments. We expect that the major outcome of these projects will be the identification of mechanisms by which SREBPs regulate intestinal growth and tumor formation. This outcome will have positive translational impact because it is feasible that the newly-identified lipid regulators will represent novel therapeutic targets that could be manipulated pharmacologically. It is feasible that these novel lipid signals will represent drug targets for the treatment of colon cancer, which is the 3rd most common cause of cancer death in the U.S. and an emerging health threat in Texas given the recent, very concerning increase in colon cancer in younger populations. Lastly, we hope that a better understanding of lipid metabolism in the intestine will facilitate the development of new treatments for complications of obesity like NAFLD, which is epidemic in the U.S.