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Endosomal Platforms for Neuropeptide Receptor Signaling

神经肽受体信号转导的内体平台

基本信息

批准号：
9755538
负责人：
NIGEL W BUNNETT
金额：
$ 6.7万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2019-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9755538
关键词：
Acute Pain Afferent Neurons Agonist Awareness Behavior Biophysics Calcitonin Gene-Related Peptide Calcitonin-Gene Related Peptide Receptor Cell Surface Receptors Cell membrane Cell surface Clathrin Clinical Clinical Trials Complex Conscious Diabetes Mellitus Disease Dynamin Electrophysiology (science)Endocytosis Endosomes Failure Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Generations Image Inflammatory Bowel Diseases Injury Irritable Bowel Syndrome Lipids Mediating Medical Membrane Multiprotein Complexes Mus Neurons Neuropeptide Receptor Neuropeptides Nociception Nociceptors Outcome Pain Pain management Pancreatitis Pathologic Pathologic Processes Persistent pain Pharmaceutical Preparations Pharmacology Physiological Physiological Processes Plasma Process Proteins Proteomics Receptor Signaling Role Signal Transduction Signaling Protein Site Slice Small Interfering RNA Spinal Spinal Cord Spinal cord posterior horn Stimulus Substance P Substance P Receptor Therapeutic Time Tissues Transgenic Mice afferent nerve beta-arrestin calcitonin receptor-like receptor central pain chemotherapy chronic pain clinical efficacy defined contribution effective therapy experimental study genetic approach inhibitor/antagonist injured knock-down member nanoparticle pain signal receptor receptor recycling side effect targeted treatment therapeutic target transmission process

项目摘要

PROJECT SUMMARY This proposal examines the mechanisms by which G protein-coupled receptors (GPCRs) signal pain. Chronic pain is a hallmark of disease, a side effect of therapy, and a major cause of suffering. Although GPCRs mediate all aspects of nociception and are major therapeutic targets, the mechanisms by which GPCRs signal sustained pain are poorly understood, and clinical trials of GPCR antagonists in chronic pain often fail for unexplained reasons. The proposal challenges three dogmas that contribute to this lack of understanding: 1. GPCRs signal only from the cell-surface. 2. Endosomes are merely a conduit for GPCR recycling or degradation. 3. Cell-surface GPCRs are the optimal therapeutic target. The proposal hypothesizes that: 1. Endosomal GPCRs generate sustained signals that mediate persistent excitation of spinal neurons and nociception. 2. Targeting endosomal rather than cell-surface GPCRs is the ideal therapeutic strategy, and the clinical failure of conventional antagonists relates to their inability to inhibit endosomal receptors. Experiments will focus on substance P and calcitonin gene-related peptide receptors, which mediate central pain transmission and are internalized after painful stimuli. The contribution of receptor endocytosis to nociception will be evaluated using pharmacological and genetic approaches to disrupt clathrin, dynamin and β-arrestin, and by studying transgenic mice expressing non-internalizing receptors. Lipid-conjugation and nanoparticle- encapsulation will be used to deliver antagonists to endosomal GPCRs. Aim 1 will determine the contribution of endocytosis to somatic and colonic nociception in conscious mice. Aim 2 will define the importance of endocytosis for excitation of spinal neurons, which will be analyzed in intact tissues using electrophysiology. Aim 3 will determine the requirement of endocytosis for the generation of signals in subcellular compartments that underlie neuronal excitation and nociception, which will be studied in isolated neurons using biophysical, imaging and proteomic approaches. The results will provide fundamental information about pain signaling and therapy. Since GPCRs are the largest class of signaling proteins and the target of one half of therapeutic drugs, the outcomes will be broadly significant.

项目总结