THE ROLE OF PKA IN GRPR DESENSITIZATION

 描述（由申请人提供）：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体征。慢性瘙痒在很大程度上对传统的抗组胺药有抵抗力，并且几乎没有有效的治疗方法。为了开发针对慢性瘙痒的新疗法，迫切需要鉴定抑制慢性瘙痒的信号传导机制。我们已经表明，胃泌素释放肽受体（GRPR）是一个重要的受体的发展慢性瘙痒。最近，我们发现PKA激活通过抑制GRPR功能来减轻瘙痒。目的1是确定PKA激活是否通过阻断GRPR功能来抑制瘙痒。目的二是研究PKA在GRPR磷酸化中的作用。拟议的研究是高度翻译的，因为它将提供PKA介导的瘙痒传播抑制机制的见解，并可能扩大可能用于设计新的PKA激活为基础的止痒疗法的目标池。

 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 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.