Research Description
Motor neurons in the hindbrain's dorsal motor nucleus of the vagus (DMV) mediate parasympathetic control of digestion, insulin release, and hepatic glucose production. Understanding how these DMV neurons function, including what receptors and signaling molecules they express, will reveal novel targets and strategies for diabetes treatment. Furthermore, since DMV provides most of the brain's control of gut motility, including two DMV neuron populations that oppositely affect gastric muscle tone, its dysregulation in diabetes may underlie gastroparesis. However, while DMV has been shown to be anatomically and functionally diverse, little is known about its genetic diversity. We therefore profiled gene expression in 304 DMV motor neurons individually, detecting 7,873 +/- 1,298 unique transcripts per neuron (mean +/- standard deviation). Unsupervised clustering revealed nine transcriptionally-distinct types of DMV motor neurons and specific markers that enable genetic access to each type. We will now extend these studies by using Drop-seq to profile genome-wide expression in thousands of neurons in/around DMV and comprehensively catalog neuron types. Then, using recombinase-based genetic technology, we will determine where each DMV neuron type projects by fluorescently labeling its axons and imaging innervated organs. Once we have mapped where each DMV neuron type projects, we will assess its physiological role by manipulating its activity in vivo while measuring organ functions, including gastric tone and blood insulin. By defining the gene expression profile, neurocircuitry, and physiological role of each vagal motor neuron type, these studies will yield unprecedented insight into the cellular and molecular control of digestion and glucose metabolism.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?My project focuses on how vagal motor neurons control glucose metabolism and digestion, areas of interest to diabetes research. By defining the neural circuitry and signaling molecules by which these vagal motor neurons drive insulin release and gastric motility, my project may reveal new therapeutic targets for treating diabetes and diabetic gastroparesis.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?My project aims to identify neuron subtypes that relay information from the brain to the digestive system, including the pancreas. Identifying these neurons and how they signal to their target organs in the gut will lead to better treatments for diabetes. For instance, by discovering the signaling molecules and receptors these neurons use to control pancreatic insulin release and gastric motility, respectively, new drugs can be developed to target those receptors and treat diabetes and diabetic gastroparesis.
Why important for you, personally, to become involved in diabetes research? What role will this award play?The prevalence of diabetes in the US is high and rising, which makes diabetes treatment an issue of increasing urgency. Personally, it is important to me that my research addresses this urgent issue by discovering new opportunities to treat diabetes. The ADA Pathway to Stop Diabetes (Initiator) award will be vital to both the growth and direction of my diabetes research efforts. Specifically, it will enable my transition to independent research while simultaneously launching a major study of how the vagal motor system controls glucose metabolism and digestion, a focus central to my ongoing and future research plans.
In what direction do you see the future of diabetes research going?One direction for the future of diabetes research will be the rational design of pharmacological treatments for diabetes. With recent technological advances in molecular research methods (single-cell RNA-Seq, CRISPR/Cas9), cell types and signaling pathways that control glucose metabolism can now be rapidly and systematically identified. Projects such as mine that use gene expression as a basis for identifying cell types and their physiological function will help to uncover novel signaling pathways in glucose homeostasis. These signaling pathways can then be targeted to develop new treatments for diabetes.