D1R/Shp-2复合物在异动症大鼠 D1R/ERK/mTORC1 通路中的作用

帕金森病异动症（LID）是临床治疗的难点，发病机制尚不明确。既往研究证明在纹状体中D1受体超敏介导ERK过度激活参与LID的发生。新近研究发现培养细胞中全新促发D1受体介导ERK激活的新机制，涉及络氨酸磷酸酶Shp-2，与D1受体共同调节D1R/ERK/mTORC1信号通路。本课题旨在动物模型中研究D1受体和Shp-2之间的相互作用，明确D1受体/Shp-2复合物的存在；结合D1受体激动剂和拮抗剂、左旋多巴缓释微球和特异性D1受体、Shp-2结合的干扰肽，观察D1受体/Shp-2复合物在调节D1R/ERK/mTORC1信号通路中的作用，以明确其在帕金森病左旋多巴诱导异动症发生机制中所扮演的角色，并对其可能成为一个新的潜在治疗靶点提供依据。

L-dopa therapy for Parkinson's disease leads to dyskinesias for which there are few treatment options. The pathogenesis and management of LID remain unclear. Accumulating evidence indicates that LID develops in response to activation of sensitized D1Rs and modifications of ERK signaling pathway. One study has recently identified a new mechanism for D1R-mediated activation of ERK1/2 in striatal neurons involving the tyrosine phosphatase Shp-2. In particular, in the striatum, Shp-2 directly interacts with the D1R and is activated by D1R stimulation which is essential for D1R/ERK/mTORC1 signaling pathway. In this study, we aim to investigate the role of the D1R/Shp-2 complex in L-Dopa-induced aberrant activaion of ERK1/2 signaling and development of dyskinesia in the 6-OHDA rat model of PD, using D1 receptor agonists and antagonists, levodopa microspheres and injection of peptides specifically disrupting striatal D1R/Shp-2 interaction. We aim to define the role of the D1R/Shp-2 complex in the development of LID since it could represent a promising new drug target for LID.