Grant: $504,186 - National Institutes of Health - Sep. 11, 2009
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Award Description: Sensing of luminal contents by the gastrointestinal (GI) mucosa plays a critical role in the regulation of digestive functions and protection from harmful substances. Different chemicals in the lumen (nutrients, drugs, pathogens, toxins) are detected by different detector systems including enteroendocrine cells, which release hormones entering the circulation, or signaling molecules activating different neuronal pathways. Enteroendocrine cells serve as specialized transducers and represent the first line of integration of chemosensing in the gut. Detection of nutrients or non-nutrients initiates a cascade of events regulating digestion, absorption, food intake, and metabolism, or generates defense processes like food avoidance, neutralization and expulsion of harmful substances. However, the molecular recognition events underlying chemosensing in the gut are still elusive. The recent discovery that taste receptors, (T1Rs for sweet and T2Rs for bitter) and the G-proteins subunits, alpha-gustducin and alpha-transducin, mediating gustatory signals in the tongue are localized to the GI mucosa and that alpha-gustducin colocalizes with CCK and PYY, peptides that affect GI function and food intake, is supportive of the concept that 'tasting' occurs in the gut, where taste receptors are likely to participate in the functional detection of intraluminal substances and initiate a functional appropriate responses. Bitter taste in the mouth has evolved as a warning signal against the ingestion of potentially toxic ('bitter') substances. Initial findings that intraluminal bitter ligands induce activation of vagal afferent neurons suggest that taste signaling molecules participate in the functional detection of harmful substances in the lumen and possibly initiate protective responses. This application will focus on bitter taste receptors in the gut and will test the hypothesis that bitter taste signaling molecules in the gut represent a second line of defense versus harmful substances like pathogens, toxins, drugs and promote a protective response by releasing enteroendocrine hormones that change GI functions to reduce the damage of toxic substances. The proposal is that stimulation of bitter chemosensory receptors in the GI mucosa induces release of signaling molecules by enteroendocrine cells that activate vagal afferent neuronal pathways to modulate GI function and food intake. The long term goal is to develop an understanding of the mechanisms regulating luminal chemosensing, an important physiological process for the regulation of GI function and the detection of ingested harmful drugs and toxins that could initiate responses critical for survival. Understanding chemosensory processes has clinical implications since aberrant or unsteady responses to changes in luminal content might result in disease states ranging from intoxication to feeding disorders and inflammation.
Project Description: This application is aimed at determining 1a) the effects and site of action along the gut of intraluminal T2R agonists on vagal afferent pathways and the role of CCK and PYY, peptides that affect GI function and feeding behavior, acting at CCK1 and Y2 receptors on vagal afferents, and 1b) the effects of T2R agonists on vagal pathways using electrophysiological recording of vagal afferents innervating the stomach and duodenum in vivo. Specific Aim 2 will establish the functional significance of the stimulation of gastrointestinal T2Rs and their regulation by feeding by determining 2a) the changes in food intake and aversion behavior in response to T2R subtype agonists and whether these effects are mediated by alpha-gustducin, 2b) the effect of feeding, and fasting on the expression levels of alpha-gustducin and selected T2Rs, and 2c) the signal transduction pathways initiated by T2R agonists in enteroendocrine STC-1 cells in vitro, and whether intraluminal T2R agonists activate endocrine cells in situ using immunohistochemistry for phosphorylated calmodulin dependent kinase 2 (CAMK2) as a marker for intracellular Ca2+ elevation. We expect that different bitter ligands activate distinct neuronal pathways that could be responsible for aversive responses. We anticipate that bitter activation will affect GI function including inhibition of motility and increase in secretion and that intraluminal T2R agonists will lead to inhibition of food intake and increased intestinal secretion. The studies investigating how expression of G proteins and T2Rs is altered by physiological changes in the intestine, such as feeding or fasting, will provide information on mechanisms controlling chemosensing molecules. Furthermore, determining whether T2R ligands affect the synthesis and expression of their receptors will establish whether T2Rs can be regulated by specific components in the diet.
Infrastructure Description: N/A.
Jobs Summary: Not Applicable (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 11, 2009. Help expand these official descriptions using the wiki below.
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