GPCR-mediated pathways for regulation of intestinal lymphatic function

GPCR 介导的肠道淋巴功能调节途径

基本信息

批准号：
9884761
负责人：
Kathleen M Caron
金额：
$ 51.75万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884761
关键词：
Accounting Address Adherence Adult Animal Model Autonomic nervous system Biochemical Bioinformatics Cells Clinical Communication Complex Disease Drug Targeting Dysplasia Embryo Endocrine Enteroendocrine Cell Failure to Thrive G-Protein-Coupled Receptors Gastrointestinal tract structure Genes Genetic Genomics Goals Grant Health Hormones Human Human Development Hydrops Fetalis Inflammatory Inflammatory Bowel Diseases Intestinal Diseases Intestines Knockout Mice Laboratories Ligands Light Limb structure Lipids Lymphangiectasis Lymphangiogenesis Lymphatic Mediating Mediator of activation protein Metabolic Diseases Metabolic syndrome Modern Medicine Molecular Molecular Chaperones Monomeric GTP-Binding Proteins Mus National Institute of Diabetes and Digestive and Kidney Diseases Nerve Nutrient Obesity Orphan Pathway interactions Pharmacologic Substance Pharmacology Phenotype Physiological Play Prevalence Protein-Losing Enteropathies Proteins Proteomics Regulation Role Signal Transduction Study models System Tamoxifen Therapeutic Tissues United States National Institutes of Health Vascular System absorption adrenomedullin base calcitonin receptor-like receptor combat design detection of nutrient dietary constituent gastrointestinal system human disease improved in vivo insight lipid metabolism lipid transport loss of function mutation lymphatic vessel mature animal novel preservation receptor response spatiotemporal therapeutic target uptake

项目摘要

Abstract G protein-coupled receptors (GPCRs) represent the largest class of pharmacological targets in modern medicine, accounting for over 60% of all prescriptions worldwide. Yet, of the ~345 non- olfactory GPCRs, many remain either orphan (with no known ligand) or uncharacterized (with no clear physiological function). Therefore, discovering the spatiotemporal regulation and function of GPCRs within pharmaceutically- and physiologically-understudied systems is of great clinical importance. Considering the essential role of lymphatic vessels in intestinal lipid absorption and the increased prevalence of inflammatory and metabolic diseases of the intestine, it is rather remarkable that there are currently more questions than answers regarding whether and/or how lymphatic vessels contribute to normal digestive function and/or diseases in adults. Therefore, studies proposed in this grant have been purposefully designed to address numerous key questions raised by the recent NIH/NIDDK-sponsored RFA-DK-17-016 entitled: Lymphatics in Health and Disease in the Digestive System. Using state-of-the-art biochemical, proteomic, genomic and animal model approaches, we propose to build on our current expertise on the CLR-AM signaling axis within the lymphatic vascular system. Ultimately, we hope our studies will expand the repertoire of GPCR pathways that play important functions in the regulation of the neurolymphocrine unit within the GI tract, and potentially uncover unique and pharmacologically-tractable pathways for the improvement of digestive health.

抽象的 G 蛋白偶联受体 (GPCR) 代表了最大类别的药理学靶点现代医学，占全球所有处方的 60% 以上。然而，在大约 345 个非嗅觉 GPCR，许多仍然是孤儿（没有已知的配体）或未表征的（没有明确的配体）生理功能）。因此，发现GPCRs的时空调控和功能在药物和生理学研究系统中具有重要的临床意义。考虑到淋巴管在肠道脂质吸收中的重要作用以及增加的肠道炎症和代谢性疾病的流行，值得注意的是目前关于淋巴管是否存在和/或如何存在的问题多于答案有助于成人的正常消化功能和/或疾病。因此，本研究提出的研究赠款的目的是为了解决最近提出的许多关键问题 NIH/NIDDK 赞助的 RFA-DK-17-016，标题为：健康中的淋巴管和消化道疾病系统。使用最先进的生化、蛋白质组、基因组和动物模型方法，我们建议以我们目前在淋巴管内 CLR-AM 信号轴的专业知识为基础系统。最终，我们希望我们的研究能够扩展发挥作用的 GPCR 通路的全部内容。调节胃肠道内神经淋巴细胞单位的重要功能，并可能发现改善消化健康的独特且药理学上可控制的途径。