Collaborative Research: Integrative mechanisms underlying the regulation of intestinal form and function

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The small intestine is the principal gateway for the uptake of nutrients from meals, the largest of the body's endocrine and immune organs, and hosts an immense bacterial community that is thought to influence all realms of the body's physiology. The intestine also can remodel its structure and function to match meal size, to accommodate changes in diet, and to compensate for loss due to disease or surgery, but little is currently known about the precise mechanisms that underlie this remodeling. The ultimate goal of this collaborative research is to identify the signaling and structural mechanisms that enable the vertebrate intestine to modulate structure and function. Rather than relying on traditional laboratory research animals to achieve this goal, this program takes advantage of the extreme ability of some snakes (pythons, boas, and rattlesnakes) to remodel their small intestine with each meal. By comparing the cellular and molecular responses of the small intestine to feeding and fasting among snakes that feed regularly versus sporadically, and between snakes and other vertebrates, coupled with available genomic resources, this research program will provide new insight into the mechanisms that underlie intestinal remodeling in vertebrates. An exciting novelty of this research is the incorporation of non-traditional model species (i.e., snakes) that have the potential to reveal previously unknown or overlooked mechanisms and that may be important for driving new discoveries for the therapeutic treatment of intestinal diseases. The project's outreach components include workshops on the generation and analyses of gene expression data, and public lectures and animal-based exhibitions to local schools, camps, and museums.Vertebrates possess the physiological capacities to alter intestinal performance that are adaptively linked to their feeding habits. For example, species that naturally experience long episodes of fasting between large meals (e.g., sit-and-wait foraging snakes) experience rapid upregulation of intestinal form and function with feeding, and subsequent intestinal atrophy and downregulation following digestion. In contrast, frequently feeding species (e.g., active-foraging snakes) experience only modest change in intestinal form and function with each meal. Currently unknown are the cellular and molecular mechanisms that underlie the structural and functional flexibility of the intestine, and whether such mechanisms are shared across vertebrates that widely or narrowly regulate intestinal performance. By leveraging the extreme range in intestinal responses exhibited by snakes and other vertebrates, and recently available genomic resources, this research program will identify the underlying mechanisms of intestinal flexibility and. test whether these mechanisms are shared across lineages and regulatory phenotypes. This goal will be accomplished by pursuing three aims: (1) identify the cellular and structural mechanisms that underlie the modulation of intestinal form, and whether form dictates the regulation of intestinal function; (2) link transcriptional and post-translational mechanisms to phenotypic changes in intestinal structure and function; and (3) test whether shared or unique sets of molecular mechanisms drive similar phenotypic responses among vertebrates. Ultimately, this research will identify the signaling and structural mechanisms by which vertebrates modulate intestinal form and function.