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Biased sweet taste signaling pathways in mice and humans

小鼠和人类中偏向的甜味信号通路

基本信息

批准号：
10456040
负责人：
Sunil Kumar Sukumaran
金额：
$ 13.26万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456040
关键词：
3D Print ARRB1 gene Adaptor Signaling Protein Animal Model Arrestins Attention Behavioral Binding Biological Assay Biological Models Biopsy Calories Cells Consumption Data Development Disease Endocytosis Energy Transfer Food Fructose Future G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Gene Expression Profile Genes Genomics Goals Grant Growth Factor Growth Factor Receptors Health Benefit Human Immunohistochemistry In Situ Hybridization Industry Inferior Kinetics Ligands MAPK3 gene Measures Mediating Mediator of activation protein Methods Microscopic Mitogen-Activated Protein Kinases Mus Natural regeneration Nebraska Nerve Obesity Epidemic Organoids Pathway interactions Pharmacology Phosphorylation Physiological Play Positioning Attribute Role Saccharin Signal Pathway Signal Transduction Stream Sucrose Sugar Substitute Sweetening Agents Tamoxifen Taste Buds Taste Perception Taste preferences Testing Tissues United States National Institutes of Health Western Blotting base cell type conditional knockout desensitization design dietary drug candidate experience good diet in vivo mouse model novel novel strategies obesity prevention prevent receptor response single-cell RNA sequencing stem cell growth stem cells sugar sweet taste perception sweetened beverage taste stimuli taste system tongue papilla tool development transcriptome sequencing transcriptomics

项目摘要

The obesity epidemic has reached alarming proportions in many parts of the world, fueled by the over consumption of calorie-rich foods, primarily sugars in the form of sugar-sweetened beverages and other sweet foods. Hence, novel strategies are needed to prevent excessive sugar consumption and to promote a healthy diet. Non-caloric sweeteners have been used for several decades to replace sugar-derived calories. However, their health benefits have been questioned and their taste profile is inferior to sugars. Therefore, there is a need to develop novel healthy and tasty non-caloric sweeteners. The sweet taste receptor - a heterodimeric G-protein coupled receptor (GPCR) formed by the TAS1R2 and TAS1R3 subunits - is the primary receptor for sugars and non-caloric sweeteners. Studies to date have focused on the G-protein mediated pathway as the primary mechanism for transduction of sweet taste signaling downstream of the sweet taste receptor. However, it is now well known that the arrestins, adaptor proteins first identified as mediators of GPCR- desensitization, can transduce signals down stream of GPCRs on their own. The G-protein and arrestin pathways engage different downstream signaling partners and consequently, have different physiological effects. An exciting development in pharmacology is the discovery that some GPCR ligands differentially engage the G-protein and arrestin pathways, although they bind to the same receptor. Such biased ligands are exciting drug candidates. Using single-cell RNASeq, we showed that Arrb1 is the sole arrestin expressed in sweet taste receptor expressing cells. We propose to identify the role of arrestin signaling in sweet taste using conditional knockout (CKO) mice models and taste organoids cultured from this strain. We will confirm the specific expression of Arrb1 in sweet taste cells using in situ hybridization and immunohistochemistry and will compare the behavioral and taste nerve responses of Arrb1CKO and control mice to sweet and other control taste stimuli. The kinetics of arrestin binding to the sweet taste receptor, sweet taste adaptation, and arrestin signaling will be studied in taste organoids using microscopic and other assays (Specific Aim 1). Unfortunately, such mechanistic studies are not possible in humans, as human taste stem cells have not been identified. We will use cutting-edge spatial transcriptomics of human and mouse taste papillae and compare this to existing droplet-based scRNASeq data from mouse cells, to identify human taste cell types including stem cells and the growth factors required for regeneration of taste cells (Specific Aim 2). Data from this study will enable the development of tools and strategies to manipulate sweet taste signaling.

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