2016 Pathway Accelerator Awardee Praveen Sethupathy, PhD
Defining the Molecular Mechanisms of Intestinal Homeostasis
Project Title: Systems Approach to Defining Genetic Regulation of Intestinal Physiology and Gut Microbiota in Diet-Induced Obesity
Institution: Cornell University
Pathway Project Publications: 2
Has established three new collaborations with investigators at other institutions
Since starting the Pathway award in 2016, my laboratory has: (1) defined the microRNA landscape in several functionally-distinct cell types of the small intestinal epithelium, (2) determined the sensitivity of microRNAs in these cell types to gut microbes and high-fat diet (HFD), and (3) identified specific microRNAs that may play an important role in intestinal stem cell (ISC) homeostasis, which is critical for proper intestinal physiology and metabolic balance.
Our work shows that only a handful of microRNAs are significantly altered by the presence of gut microbes or by HFD in small intestinal enteroendocrine cells (EEC), which are critical for metabolic balance. Based on known functions of some of these microRNAs in pancreatic beta cells, we hypothesize that they may regulate the secretion of gut hormones from EECs. We also determined that microRNAs in ISCs are by far the most sensitive to gut microbial presence or HFD compared to the other cell types of the intestinal epithelium that we analyzed. Both microbial colonization and HFD have been shown to enhance intestinal epithelial proliferation. We hypothesized that this effect may be mediated at least in part by microbe- and HFD-sensitive ISC microRNAs. We performed loss-of-function studies in 3D enteroids (sometimes referred to as “mini-guts in a dish”) and demonstrated that two specific ISC microRNAs control both enteroid proliferation and EEC differentiation. Preliminary results from in vivo genetic deletion studies confirm these results, providing further support to the idea that these microRNAs are critical regulators of intestinal homeostasis.
The Pathway award has been critical for my science and my career. Scientifically, Pathway is allowing me to express some creative freedom and use a highly multi-disciplinary strategy to push the boundaries of scientific knowledge in an area of research that I believe is critical for understanding and potentially curing diabetes. The intestine has emerged as an extremely important organ in the etiology of diabetes. The rate of remission associated with bariatric surgery, which appears to bring about positive and immediate metabolic changes in large part due to alterations in intestinal physiology, as well as metformin, for which the primary mechanism of action has been localized to the lower gut, puts the intestine squarely at the center of efforts to develop novel and even more effective molecular therapies. It is critical that we dig deeper to understand the regulatory networks that help maintain intestinal homeostasis, particularly in the face of a wide range of constantly changing environmental stimuli, including nutrients, microbes, pathogenic infections, etc. My project fits precisely in this space and would likely not have been funded by more traditional mechanisms.
Career-wise, Pathway has been a tremendous boon. The funding, and the science that is on-going as a result, has led to several invited seminars across the country and lectures at international scientific conferences. I am grateful for the substantive role that Pathway has played the last year and a half in the strengthening of our research program, and I look forward to more of the same over the next three and a half years.