My lab has a keen interest in understanding gene regulation and signaling pathways in the context of gastrointestinal diseases. My clinical interests are in inflammatory bowel disease and colon cancer. The goal of the lab is to merge my interests in basic science research with my clinical pursuits.
Inflammatory bowel disease (IBD) has been associated with significant morbidity and mortality. Currently, the etiology of IBD is unknown. To date, much of the research into IBD has focused on protein-coding transcripts and the resulting protein products. Interestingly, approximately 2% of the genome is found to encode for proteins while the vast majority of RNA transcription produces non-coding transcripts. The central dogma, wherein “DNA makes RNA makes protein,” has long relegated RNA as an intermediary between gene and protein. However, recent research has challenged the notion that the non-coding RNAs are innocent bystanders and may indeed be critical to gene regulation. The non-coding RNA family includes microRNAs, telomerases, components of the spliceosome, and long non-coding RNAs (lncRNAs). LncRNAs are defined as RNA transcripts lacking open reading frames and having a length greater than 200 nucleotides. These transcripts have a diverse set of functions in chromatin remodeling, telomerase activity, and subcellular structural organization. Additionally, lncRNAs have been implicated in regulation of the inflammatory processes. To study their function, unbiased evaluations of the differentially expressed lncRNAs in IBD tissues were performed. In two separate analyses, IFNG-AS1 was found to be upregulated in IBD patients whiles CDKN2B-AS1 was found to be significantly downregulated in IBD patient samples when compared to controls. By manipulating the expression of these lncRNAs, we are dissecting the pathways affected by these genes and uncovering functions relevant to IBD biology. Our findings are expected to uncover novel mechanisms of action for lncRNAs in IBD. By focusing on these lncRNAs, we hope to show that lncRNAs can function as key regulators in IBD pathogenesis both in vitro and in vivo assays. Understanding the role of lncRNAs in IBD can serve in the development of novel diagnostic and therapeutic tools to address the morbidity associated with IBD.
In addition, the lab is also focused on studying the role of lncRNAs in colon cancer metastasis. Colorectal cancer is the third most common malignancy in both American men and women. With over 134,000 new cases diagnosed in 2016 and over 49,000 deaths attributed to colorectal cancer, this disease represents a significant challenge to our healthcare system. Most of the deaths attributed to colorectal cancer are a result of metastatic spread. Colon cancer cells target the liver in over 70% of metastatic patients utilizing complex mechanisms to travel from the primary tumor site to distant metastases. Currently, therapies directed against colorectal cancer aim to curb the spread of these metastatic cells after surgical resection. However, the efficacy of these therapies is limited. Understanding the process of metastasis will be critical in developing new tools to tackle the problem of metastatic spread. Research into the role of lncRNAs in cancer has recently uncovered a variety of functions, however their role in colon cancer metastasis specifically remains to be determined. Recent research using the colon cancer cell line, LS-147T, has identified subpopulations within the cell line that have differing metastatic capabilities. Through in vivo selection, highly metastatic subpopulations of cells that can aggressively colonize the liver in xenograft mouse models of metastasis were isolated. We have profiled these different subpopulations and identified over 200 differentially expressed lncRNAs that are associated with the aggressive metastatic phenotype. Candidate lncRNAs will be selected based on their differential expression in human clinical cohorts of colon cancer metastases. By perturbing the expression of these lncRNAs in our cell system, we aim to assay their role in liver metastasis. By altering the expression of these lncRNAs, we can dissect their function and identify downstream targets of regulation. Using a combination of in vitro and in vivo assays, we aim to develop a system to investigate key players in colon cancer metastasis. It is the hope that the information learned through these experiments can serve to develop new targets for colon cancer prognostics and therapeutics.