THE ROLE OF PKA IN GRPR DESENSITIZATION

 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。为了开发治疗慢性瘙痒的新药物，迫切需要确定抑制慢性瘙痒的信号机制。我们已经证明胃泌素释放肽受体(GRPR)是慢性瘙痒发生发展的重要受体。最近，我们发现PKA的激活通过抑制GRPR功能来减轻瘙痒。目的1确定PKA激活是否通过阻断GRPR功能而抑制瘙痒。目的2研究PKA在GRPR磷酸化中的作用。建议的研究具有很高的翻译性，因为它将为PKA介导的抑制瘙痒传播的机制提供深入的见解，并可能扩大可能被探索的靶点池，以设计基于PKA激活的新型止痒疗法。

 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 signaling mechanisms by which chronic itch is inhibited. We have shown that gastrin-releasing peptide receptor (GRPR) is an important receptor for the development of chronic itch. More recently, we found that PKA activation attenuates itch by inhibiting GRPR function. Aim 1 is to determine whether PKA activation inhibits itch by blockade of GRPR function. Aim 2 is to examine the role of PKA in GRPR phosphorylation. The proposed studies are highly translational because it will provide mechanistic insights into PKA-mediated inhibition of itch transmission and may expand the pool of the targets that might be explored for designing novel PKA activation-based anti-pruritus therapies.