UNDERSTANDING MECHANISMS THAT BLOCK GRPR-MEDIATED CHRONIC ITCH

了解阻止 GRPR 介导的慢性瘙痒的机制

基本信息

批准号：
9761603
负责人：
ZHOUFENG CHEN
金额：
$ 36.47万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761603
关键词：
Acute Antihistamines Attenuated Behavioral Biochemical Biophysics Bombesin Receptor Calcium Cells Clinical Co-Immunoprecipitations Complex Coupled Development Disease Drug Targeting Electrophysiology (science)Fluorescence Resonance Energy Transfer Foundations Future G alpha q Protein GRP gene Genetic Models Goals Image Immune system Label Laboratories Mediating Medical Membrane Modeling Molecular Mus Nervous system structure Neurons Pattern Phosphorylation Phosphorylation Site Physiological Preparation Process Protein Isoforms Proteins Pruritus Receptor Activation Receptor Cross-Talk Receptor Signaling Resistance Role Series Signal Transduction Signaling Molecule Skin Small Interfering RNA Solid Spinal Cord Stimulus Techniques Testing Therapeutic base behavior test behavioral response chronic itch combinatorial desensitization design drug discovery effective therapy imaging genetics insight interdisciplinary approach kappa opioid receptors knock-down novel novel therapeutics patch clamp programs public health relevance receptor receptor function response sensor side effect signal recognition particle receptor tool transmission process

项目摘要

DESCRIPTION (provided by applicant) Chronic itch is a presenting sign in numerous diseases associated with the skin, immune and nervous systems. Chronic itch is largely resistant to conventional antihistamines, and few effective therapies are available. In order to develop novel therapeutics against chronic itch, there is a pressing need for identification of itc-specific signaling mechanisms involved. Activation of kappa opioid receptor (KOR) can inhibit chronic itch. However, KOR activation is associated with several side effects that might have hindered its use as therapeutics. We recently found that gastrin-releasing peptide receptor (GRPR) is an important receptor for the development of chronic itch, and KOR activation attenuates itch by inhibiting GRPR function. Aim 1 is to determine whether KOR inhibits itch by a blockade of GRPR function. Aim 2 is to examine the role of PKC in KOR activation-mediated inhibition. Aim 3 is to determine whether KOR activation inhibits itch via KOR-GRPR heteromerization. The proposed studies are highly translational because it will provide mechanistic insights into KOR-mediated inhibition of chronic itch and will significantly expand the pool of the targets that may be explored for future KOR-GRPR-based anti-pruritus drug discovery program.

描述（由适用提供）慢性瘙痒是与皮肤，免疫和神经系统相关的许多疾病的表现。慢性瘙痒在很大程度上对常规抗组胺药具有抗药性，很少有有效的疗法可用。为了开发针对慢性瘙痒的新疗法，需要鉴定涉及的ITC特异性信号传导机制的迫切需求。 Kappa阿片受体（Kor）的激活可以抑制慢性瘙痒。但是，KOR激活与几种可能阻碍其用作治疗的副作用有关。我们最近发现，胃蛋白释放的肽受体（GRPR）是慢性瘙痒发展的重要受体，而KOR激活通过抑制GRPR功能会减轻瘙痒。 AIM 1是确定KOR是否通过封锁GRPR功能抑制它。 AIM 2是检查PKC在Kor激活介导的抑制中的作用。 AIM 3是确定KOR激活是否通过Kor-Grpr异构化抑制了瘙痒。拟议的研究经过高度翻译，因为它将提供对KOR介导的慢性瘙痒抑制的机械见解，并将大大扩展可能探索的目标池，以探索未来的基于Kor-Grpr的抗Pruritus药物发现计划。