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，仍然是帕金森氏症的主要治疗方法。 疾病（PD）治疗。不幸的是，随着持续使用，患者发展出非自愿的副作用， 运动，L-DOPA诱导的运动障碍（LID），这严重限制了L-DOPA的长期治疗效用。 密集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， 成功除了释放多巴胺（DA）外，多巴胺神经元还分泌许多分子进行交流 与他们的目标。所有这些因素的浓度，除了DA，必须减少在基底神经节， PD患者由于DA神经元的进行性变性。我们之前发现所有的多巴胺神经元 产生音刺猬（嘘），一种细胞营养因子，在整个生命和释放它在纹状体。在那里它激活了 G蛋白偶联受体（GPCR）smoothened（Smo），由胆碱能（ACh）中间神经元表达 在纹状体。ACh神经元最近被认为可能参与异常的神经元凋亡。 PD及相关疾病的基底神经节功能。我们实验室一致的初步工作 表明在PD的神经毒性损伤模型中Smo的药理学抑制或Shh的基因消融 两者都增加了LID在L-DOPA挑战时的脆弱性，这表明Shh信号的丢失是由于 多巴胺去神经支配可显著促进LID。 基于我们的研究结果，我们假设通过Shh激动剂治疗， PD模型在L-DOPA治疗后将延迟和/或减少运动障碍的形成。我们有两个具体目标： (A)确定Shh信号通路的全身药理学刺激（1）是否减弱LID， 和（2）减少纹状体ACh神经元中与LID相关的MAP激酶途径活化， 建立LID模型。(B)鉴定纹状体ACh神经元中选择性LID特异性基因表达变化 由Shh信号介导。 该提案是一项原理性研究的证明，提供了Smo信号转导途径作为一种治疗方法的临床前验证。 对抗运动障碍形成的靶点和纹状体胆碱能可塑性调节的新见解 虽然这个应用程序的重点是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，我们预计这项工作的积极成果将 导致R 01应用程序，将测试机制，其中Shh信号起源于DA神经元的影响 纹状体的电路结构和功能。