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L-DOPA治疗，继续是帕金森氏症 疾病（PD）治疗。不幸的是，随着持续使用的患者，患者会出现衰弱的非自愿副作用 L-DOPA诱导运动障碍（盖）的运动，严重限制了L-DOPA的长期治疗效用。 密集研究一直致力于寻找可以减少或消除盖子的治疗方法，但迄今为止没有 成功。除释放多巴胺（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。除了DA之外，所有这些因素的浓度还必须减少 PD患者由于DA神经元的进行性变性而引起的。我们以前发现所有多巴胺神经元 生成一生的细胞营养因子，生产声音刺猬（SHH），并将其释放到纹状体中。它在那里激活 G蛋白偶联受体（GPCR）平滑（SMO），由胆碱能（ACH）中间神经元表示 在纹状体中。 ACH神经元最近因其潜在参与异常神经元而被认可 在PD和相关疾病的基础神经节中的功能。我们实验室的一致，初步工作 证明在PD神经毒性病变模型或SHH遗传消融中对SMO的药理抑制作用 两者都增加了L-DOPA挑战时对盖子的脆弱性，表明由于 多巴胺神经支配可能会显着有助于盖子。 根据我们的结果，我们假设SHH激动剂在 PD模型将在L-DOPA治疗后延迟和/或减少运动障碍形成。我们有两个具体的目标： （a）确定SHH信号通路的系统性，药理刺激（1）是否减弱了盖子， （2）降低了纹状体的ACH神经元中的MAP激酶途径激活，与盖子相关，在 建立的盖子模型。 （b）在纹状体ACH神经元中选择性地识别特异性基因表达变化 由SHH信号传导介导的。 该提案是主要研究的证明，它提供了对SMO信号转导途径的临床前验证 抵抗运动障碍形成和对纹状体中胆碱能可塑性调节的新颖见解的靶标 尽管该应用集中在盖子上，但测试我们的假设的结果将对许多人产生更广泛的影响 涉及基底神经节异常功能的疾病。此外，我们预计这项工作的积极结果将会 导致R01应用，该应用将测试来自DA神经元影响的SHH信号传导的机制 纹状体中的电路结构和功能。