Our laboratory combines expertise in synthetic organic chemistry, mucosal biology, and IBD mouse models to develop novel compounds that regulate the transcription of genes involved in intestinal barrier repair and wound healing. The Ornelas lab is especially interested in the study of intestinal epithelial cells. These cells provide a physical and biochemical barrier between the host tissue and the commensal bacteria (microbiota) to maintain intestinal health. In disease, this barrier is disrupted leading to perpetuating cycles of inflammatory responses, further damaging the intestinal barrier. Our laboratory is interested in discovering endogenous and synthetic molecules that promote intestinal epithelial barrier integrity.The gastrointestinal mucosa functions as a semipermeable barrier that allows the absorption of nutrients and immune sensing while also blocking translocation of harmful antigens and microorganisms, playing a tremendous role in health. Loss of intestinal barrier function is a hallmark of inflammatory bowel disease (IBD), a series of inflammatory conditions including Crohn’s disease and ulcerative colitis affecting over 3 million people in the U.S. It is not known whether intestinal barrier loss is primarily responsible for IBD development but, it is known that barrier restoration is key for inflammatory resolution and a return to intestinal health. The overall goal of the Ornelas lab is to discover novel therapeutics that regulate biological pathways to promote intestinal barrier resolution and attenuate inflammatory responses.

One of our approaches is the use of targeted protein degradation (TPD) to regulate enzymes involved in mucosal inflammation. TPD is a novel therapeutic strategy that hijacks the cell’s own protein degradation machinery to selectively remove proteins of interest. Our laboratory is currently exploring TPD through the design and synthesis of proteolysis targeting chimeras (PROTACs) specifically targeting enzymes that regulate key transcription factors in intestinal homeostasis.

Another paramount component of intestinal health, known as the “hidden organ”, is the gut microbiota; composed of trillions of microorganisms that reside within our GI tract. The microbiota is responsible for the biosynthesis of multiple metabolites involved in gut health such as: short-chain fatty acids, indoles, secondary bile acids, vitamins, etc. Our laboratory is interested in studying the crosstalk between the microbiota and the intestinal barrier through the production of these metabolites. More specifically, we have discovered metabolite-mimicking compounds that exhibit similar and, in some cases, more potent biological activities. Metabolite-mimicry is a relatively new and understudied field that can potentially accelerate drug discovery and lead to potent drug-like molecules similar to naturally occurring metabolites.

To accomplish these studies, the Ornelas Lab utilizes synthetic organic chemistry, cell culture, mouse models of intestinal inflammation, and intestinal organoids. Our laboratory works hand in hand with the Colgan Lab and we actively collaborate with research programs on campus including, The GI and Liver Innate Immune Programs (GALIIP) and The Computational Chemistry and Biology Core Facility (CCB) at the Skaggs School of Pharmacy.

Complete List of Published Work in My Bibliography:

https://www.ncbi.nlm.nih.gov/myncbi/alfredo.ornelas.2/bibliography/public/