Molecular mechanisms of genetic susceptibility in inflammatory bowel disease (IBD):
IBD is a chronic inflammatory disorder in the gut that can cause abdominal pain, diarrhea, bloody stool, as well as disorders beyond the gut known as extraintestinal manifestations. IBD develops through a combination of genetic susceptibility and environmental factors. My research is focused on the single nucleotide polymorphism (SNP) rs1077773, which encodes a G to A base shift in a noncoding region of the genome and is associated with reduced IBD susceptibility. My previous work suggests that rs1077773 modulates the aryl hydrocarbon receptor (AHR) pathway, a signaling pathway that is critical to maintaining intestinal health. AHR is a ligand-activated transcription factor that is activated by a variety of host and environmental ligands. We found that rs1077773 alternate allele was associated with enhanced AHR transcriptional activity in intestinal epithelial cells and modulates cytokine production in macrophages. This suggests rs1077773 directly impacts cellular functions that are relevant to IBD pathogenesis in a ligand- and genotype- dependent, or pharmacogenomic, manner. Our current work seeks to bridge the gap between genetic susceptibility and cellular functions to define the role of pharmacogenomic loci in IBD pathogenesis.

Molecular mechanisms of resection-associated liver disease:
Trauma or therapeutic resection of the intestine can lead to intestinal insufficiency known as short bowel syndrome (SBS). A significant comorbidity in pediatric SBS patients is liver steatosis and fibrosis known as intestinal failure-associated liver disease (IFALD). Multiple risk factors contribute to IFALD including extended parenteral nutrition (PN), length of bowel resected, and microbial sequelae such as small bowel bacterial overgrowth; however, the underlying factors driving liver disease are not known. Our group utilizes a PN-independent murine resection model pioneered by Dr. Warner and colleagues to dissect the intrinsic factors that contribute to liver disease. Using single nuclear RNA-Seq, we identified a unique subset of hepatocytes characterized by Annexin A2 (Anxa2) expression with upregulated molecular programs associated with liver injury and regeneration. Anxa2 has emerged as a factor regulating injury response in the liver, and its role in chronic liver disease is still being explored. Our recent study demonstrates that mice with Anxa2 deletion (knockout mice) are protected from liver injury, suggesting a pathogenic role in IFALD. Another distinguishing feature in Anxa2+ hepatocytes is upregulation of Neuregulin 1 (Nrg1), which is also detectable in mouse serum 2 weeks after resection. The role of Nrg1 in liver biology is not fully clear, though it has been implicated as both a diagnostic and a predictive biomarker in the progression of metabolic syndrome-associated steatotic liver disease (MASLD) to hepatocellular carcinoma (HCC). Our future work is focused on exploring these molecular changes in the development of liver disease and tumorigenesis. Our long-term goal is to identify novel therapeutic approaches to prevent IFALD in SBS patients, with potentially broader applicability to other chronic liver diseases.

Microbial metabolism in the pathogenesis of chronic liver disease:
Changes in microbial composition and function, known as dysbiosis, are observed in SBS patients and in mice, but the contribution of dysbiosis to disease pathology is not fully known. Mice lacking the lipopolysaccharide receptor TLR4 are protected from resection-associated liver disease, as are mice pre-treated with vancomycin, suggesting dysbiosis contributes to the pathogenesis of liver disease. Using liquid chromatography and tandem mass spectroscopy we have identified several microbial metabolites associated with liver disease following intestinal resection, including p-cresol glucuronide, p-cresol sulfate, and indoxyl sulfate. These are microbial metabolites of amino acids tyrosine and tryptophan, respectively, and have known toxicity in the context of heart and kidney diseases. Our current work is investigating the changes in microbial metabolism that are associated with intestinal resection, and the role of their metabolites in development and progression of chronic liver disease.

I am an active member and advisor in the Mentorship to Enhance Diversity in Academia (MEDA) program. Our mission is to enhance the training experience and long term success of trainees from underrepresented groups in the STEM fields through purposeful connection to mentors, sponsorship, and development of a supportive community.

I learned through my own experience that mentorship is essential for a successful career in academia. As such, I have dedicated considerable effort to mentorship, especially in training the next generation of scientists. At the Washington University School of Medicine, I have had the privilege of teaching and mentoring over 10 trainees, ranging from undergraduate students to postdoctoral fellows. I remain active in mentorship training programs within and outside of the institution. Two examples of such programs are the Center for the Improvement of Mentored Experience in Research through the Office of Postdoctoral Affairs and the Raising a Resilient Scientist program offered by the National Institutes of Health.

Another long-term goal while at the Washington University in St. Louis School of Medicine has been to improve the retention of scientists traditionally underrepresented in medicine and research. In 2015, a taskforce was formed by the Department of Medicine with the goal of fostering an equitable and supportive training environment for all scientists through structured mentorship, resources, and personalized career development. I contributed to this process by proposing literature-based mentorship methods, assisting in funding applications, and helping with faculty mentor recruitment. The eventual outcome was the Mentorship to Enhance Development in Academia (MEDA) program. At the inaugural event in 2022, we signed up over 50 trainees for the program, with steady increases in participation since. I've remained involved as a mentor and participant in the program since.