Activation of the GPCR Smoothened as a treatment of L-Dopa Induced dyskinesia

GPCR 激活平滑化治疗左旋多巴引起的运动障碍

• 批准号: 9302564
• 负责人: Andreas H Kottmann
• 金额: $ 19.63万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302564
• 关键词: Ablation; Acetylcholine; Acute; Adjuvant Therapy; Adult; Adverse effects; Affinity Chromatography; Agonist; Alleles; Alpha Cell; Anatomy; Attenuated; Back; Basal Ganglia; Bradykinesia; Brain Diseases; Cell Survival; Cells; Chimeric Proteins; Chronic; Complement; Complex; Corpus striatum structure; Data; Denervation; Deterioration; Disease; Dopamine; Dorsal; Dose; Dyskinetic syndrome; Equilibrium; G-Protein-Coupled Receptors; Gene Expression; Gene Expression Alteration; Genetic; Hypersensitivity; Injection of therapeutic agent; Intake; Interneurons; Involuntary Movements; L-DOPA induced dyskinesia; Laboratories; Lasers; Lateral; Lesion; Levodopa; Life; Locomotion; MAP kinase activator; Mediating; Messenger RNA; Modeling; Molecular; Molecular Probes; Mus; Nerve Degeneration; Neurons; Parkinson Disease; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Polyribosomes; Publishing; Regulation; Replacement Therapy; Research; Ribosomes; SHH gene; Severities; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Structure; Technology; Test Result; Testing; Therapeutic; Tissues; Validation; Work; aphakia mice; base; cholinergic; cholinergic neuron; comparative; desensitization; dopaminergic neuron; experimental study; falls; insight; intersectionality; motor learning; mouse model; neurotoxic; new therapeutic target; novel; pre-clinical; response; smoothened signaling pathway; success

Dopamine replacement therapy, specifically L-DOPA treatment, continues to be the mainstay in Parkinson's Disease (PD) treatment. Unfortunately, with continued use patients develop debilitating side-effects of involuntary movements, L-DOPA induced dyskinesia (LIDs), which severely limit the long-term therapeutic utility of L-DOPA. Intensive research has been devoted to finding a treatment that can reduce or eliminate LIDs, but to date without success. In addition to releasing dopamine (DA), dopamine neurons secrete a number of molecules to communicate with their targets. The concentration of all of these factors, in addition to DA, must diminish in the basal ganglia of PD patients due to the progressive degeneration of DA neurons. We previously found that all dopamine neurons produce sonic hedgehog (Shh), a cell trophic factor, throughout life and release it in the striatum. There it activates the G-protein coupled receptor (GPCR) smoothened (Smo), which is expressed by cholinergic (ACh) interneurons in the striatum. ACh neurons have recently been recognized for their potential involvement in aberrant neuronal function in the basal ganglia of PD and related diseases. Consistent, preliminary work from our laboratory demonstrates that pharmacological inhibition of Smo in a neurotoxic lesion model of PD or genetic ablation of Shh both increase vulnerability to LIDs upon L-DOPA challenge, suggesting that the loss of Shh signaling due to dopamine denervation may significantly contribute to LID. Based on our results, we hypothesize that complementation of reduced Shh signaling by Shh agonist treatment in models of PD will delay and/or reduce dyskinesia formation upon L-DOPA treatment. We have two specific aims: (A) Determine whether the systemic, pharmacological stimulation of the Shh signaling pathway (1) attenuates LIDs, and (2) decreases MAP kinase pathway activation in ACh neurons of the striatum which is associated with LIDs, in established models of LIDs. (B) Identify LID specific gene expression changes selectively in striatal ACh neurons that are mediated by Shh signaling. This proposal is a proof of principle study that offers preclinical validation of the Smo signal transduction pathway as a target for counteracting dyskinesia formation and novel insights into the regulation of cholinergic plasticity in the striatum Although this application is focused on LIDs, results from testing our hypotheses will have broader implications for many disorders involving abnormal function of the basal ganglia. Further, we anticipate that positive results from this work will lead to an R01 application that will test the mechanisms by which Shh signaling originating from DA neurons influences circuit structure and function in the striatum.

多巴胺替代疗法，特别是左旋多巴治疗，仍然是帕金森病的支柱 疾病（PD）治疗。不幸的是，随着继续使用，患者会出现非自愿的使人衰弱的副作用。 运动，左旋多巴诱发运动障碍（LID），这严重限制了左旋多巴的长期治疗效用。 深入的研究一直致力于寻找一种可以减少或消除 LID 的治疗方法，但迄今为止还没有 成功。除了释放多巴胺 (DA) 之外，多巴胺神经元还分泌许多分子进行交流 和他们的目标。除 DA 外，所有这些因子的浓度在基底神经节中都必须减少。 PD患者由于DA神经元进行性退化所致。我们之前发现所有的多巴胺神经元 在整个生命过程中产生声波刺猬 (Shh)，一种细胞营养因子，并将其释放到纹状体中。在那里它激活 G 蛋白偶联受体 (GPCR) 平滑 (Smo)，由胆碱能 (ACh) 中间神经元表达 在纹状体中。 ACh 神经元最近被认为可能参与异常神经元 PD 及相关疾病的基底神经节的功能。我们实验室的一致初步工作 证明在 PD 神经毒性病变模型中对 Smo 进行药理学抑制或对 Shh 进行基因消融 两者都增加了 L-DOPA 挑战后对 LID 的脆弱性，表明由于 多巴胺去神经可能显着促进 LID。 根据我们的结果，我们假设 Shh 激动剂治疗对减少的 Shh 信号进行补充 PD模型将延迟和/或减少左旋多巴治疗后运动障碍的形成。我们有两个具体目标： (A) 确定 Shh 信号通路 (1) 的全身药理学刺激是否会减弱 LID， (2) 减少纹状体 ACh 神经元中与 LID 相关的 MAP 激酶通路激活， 建立了 LID 模型。 (B) 选择性识别纹状体 ACh 神经元中 LID 特异性基因表达变化 由Shh信号介导。 该提案是一项原理研究证明，为 Smo 信号转导通路作为一种药物提供了临床前验证。 对抗运动障碍形成的目标和对纹状体胆碱能可塑性调节的新见解 虽然这个应用程序主要关注 LID，但测试我们假设的结果将对许多人产生更广泛的影响。 涉及基底神经节功能异常的疾病。此外，我们预计这项工作将取得积极成果 导致 R01 应用程序将测试源自 DA 神经元的 Shh 信号传导的影响机制 纹状体中的电路结构和功能。