UNDERSTANDING MECHANISMS THAT BLOCK GRPR-MEDIATED CHRONIC ITCH

 描述(申请人提供)慢性瘙痒是许多与皮肤、免疫和神经系统相关的疾病的症状。慢性瘙痒在很大程度上对传统的抗组胺药物具有耐药性，而且几乎没有有效的治疗方法。为了开发新的治疗慢性瘙痒的方法，迫切需要确定ITC所涉及的特定信号机制。激活kappa阿片受体(KOR)可抑制慢性瘙痒。然而，KOR的激活与几种副作用有关，这些副作用可能会阻碍其作为治疗手段的使用。我们最近发现胃泌素释放肽受体(GRPR)是慢性瘙痒发生发展的重要受体，KOR的激活通过抑制GRPR功能来减轻瘙痒。目的1是确定KOR是否通过阻断GRPR功能而抑制瘙痒。目的2是研究PKC在KOR激活介导的抑制中的作用。目的3是确定KOR激活是否通过KOR-GRPR异构化抑制瘙痒。拟议的研究具有很高的翻译性，因为它将为KOR介导的慢性瘙痒抑制提供机械性见解，并将显著扩大未来基于KOR-GRPR的止痒药物发现计划可能探索的靶点池。

 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.