M4 muscarinic acetylcholine receptor signaling as a potent regulator of motor deficits

M4 毒蕈碱乙酰胆碱受体信号传导作为运动缺陷的有效调节剂

• 批准号: 9891115
• 负责人: Mark S Moehle
• 金额: $ 8.61万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891115
• 关键词: Acetylcholine; Advisory Committees; Anatomy; Animal Model; Antiparkinson Agents; Basal Ganglia; Behavior; Behavioral; Biochemical; Biochemistry; Cell Nucleus; Cells; Corpus striatum structure; Coupling; Cyclic AMP; DA10; Data; Data Reporting; Disease; Doctor of Philosophy; Dopamine; Dopamine D1 Receptor; Dystonia; Electrophysiology (science); Eligibility Determination; Equilibrium; G Protein-Coupled Receptor Signaling; GTP-Binding Proteins; Genetic; Genetic study; Goals; Interdisciplinary Study; Interneurons; Learning; Lesion; Link; Location; Locomotion; Mediating; Mediation; Midbrain structure; Modeling; Molecular Probes; Motor; Motor Activity; Movement Disorders; Mus; Muscarinic Acetylcholine Receptor; Neurons; Output; Parkinson Disease; Pathway interactions; Periodicity; Pharmacology; Phenotype; Play; Production; Publications; Receptor Signaling; Regulation; Reporting; Research; Research Personnel; Role; Running; Scanning; Series; Severities; Signal Transduction; Source; Substantia nigra structure; Techniques; Testing; Training; Viral; behavioral pharmacology; cholinergic; disability; dopaminergic neuron; experience; experimental study; interest; knock-down; loss of function mutation; meetings; motor behavior; motor deficit; motor disorder; motor symptom; nervous system disorder; novel; novel therapeutics; pre-clinical; predictive modeling; receptor; side effect; skills; tool

Candidate: My long term goal is to become an independent investigator running an interdisciplinary and collaborative research team to understand the mechanisms and novel treatments of neurological disorders. Specifically, my interests surround understanding how different sources of acetylcholine (ACh, i.e. cholinergic interneurons verse pedunculopontine nucleus) regulate motor dysfunction, as well as how imbalanced dopamine (DA) and M4 muscarinic acetylcholine receptor (mAChR) signaling exacerbates motor dysfunction. I have a strong background in biochemistry and electrophysiology. I propose to learn behavioral and voltammetry techniques to round out my training, and have the necessary skills to produce high impact publications and successful R01 submissions. I received my Ph.D. in April 2015, this is my last year of eligibility for the K99/R00. Training: In addition to Dr. Conn, I have an advisory committee of experts in behavioral pharmacology, Dr. Jones, dystonia and dopaminergic signaling, Dr. Ehrlich, and in using molecular probes to understand GPCR signaling, Dr. Lindsley. This committee will provide the necessary training and guidance to accomplish this proposal. Outside of the committee, we have identified, both at Vanderbilt and externally, courses, seminars, and meetings to provide further technical training, presentation experience, responsible conduct in research, and the necessary skills (offer negotiations, tenure, lab management, etc.) to transition to independence. Research: Anti-mAChR therapy is efficacious at reducing motor symptoms of some movement disorders, but severe side effects limit their utility. Our lab has made breakthroughs elucidating the roles of mAChRs, and found the M4 mAChR subtype diminishes DA release, signaling, and related motor behaviors. Additionally, M4 inhibition of DA signaling occurs tonically outside the striatum. This has led us to the model that when DA release or signaling is low, this allows M4 signaling to predominate, leading to motor dysfunction, and has led to our broad hypothesis that M4 antagonists will reduce motor deficits in movement disorders. While M4 activity may be a critical modulator of DA and basal ganglia activity, providing similar efficacy to non-selective mAChRs without side effects, this has not been tested. In preliminary data, we report the discovery of novel tool compounds to directly test our hypothesis, demonstrate losing D1 DA receptor signaling diminishes basal ganglia activity and produces motor deficits, and M4 activity bi-directionally modulates motor deficits. In aim 1, using animal models predictive of anti-parkinsonian efficacy, we will test how, and through what ACh sources, M4 activity modulates motor deficits. In aim 2, we will use a model of loss of D1 DA receptor signaling linked to dystonia to test how diminished DA signaling, possibly allowing M4 signaling to predominate, effects basal ganglia output and signaling. In aim 3, we will test how and where in the basal ganglia dystonia linked loss of D1 DA receptor signaling leads to motor deficits, and how M4 modulates these behaviors.

候选人：我的长期目标是成为一名独立的调查员，运行一项跨学科和 合作研究团队，了解神经疾病的机制和新的治疗方法。 具体地说，我的兴趣围绕着了解乙酰胆碱(ACh)的不同来源，即胆碱能 中间神经元(与桥脑脚核相反)调节运动功能障碍，以及如何失衡 多巴胺(DA)和M4乙酰胆碱受体(MAChR)信号通路可加重运动功能障碍。我 在生物化学和电生理学方面有很强的背景。我建议学习行为和伏安法。 技术，完善我的培训，并拥有必要的技能，以制作高影响力的出版物和 成功提交R01。我于2015年4月获得博士学位，这是我获得K99/R00资格的最后一年。 培训：除了康恩博士，我还有一个由行为药理学专家组成的咨询委员会。 琼斯，肌张力障碍和多巴胺能信号，埃尔利希博士，以及使用分子探针理解gpcr 信号，林德斯利博士。该委员会将为实现这一目标提供必要的培训和指导。 求婚。在委员会之外，我们已经在范德比尔特和外部确定了课程、研讨会、 和会议，以提供进一步的技术培训、演讲经验、负责任的研究行为、 以及必要的技能(提供谈判、终身教职、实验室管理等)过渡到独立。 研究：抗mAChR疗法对减少某些运动障碍的运动症状有效，但 严重的副作用限制了它们的应用。我们的实验室在阐明mAChRs的作用方面取得了突破，并且 发现M4 mAChR亚型减少DA的释放、信号和相关的运动行为。此外，M4 DA信号的抑制发生在纹状体外。这将我们带到了一个模型，当检察官 释放或信号低，这使得M4信号占优势，导致运动功能障碍，并已导致 我们的广泛假设是，M4拮抗剂将减少运动障碍患者的运动障碍。而M4 活动可能是DA和基底节活动的关键调节器，提供与非选择性类似的疗效 MAChRs没有副作用，这还没有经过测试。在初步数据中，我们报告了新工具的发现 化合物直接测试我们的假设，证明失去D1DA受体信号会降低基础 神经节活动并产生运动缺陷，而M4活动双向调节运动缺陷。在目标1中， 使用预测抗帕金森症疗效的动物模型，我们将测试ACh如何以及通过什么来源， M4活动调节运动缺陷。在目标2中，我们将使用与D1DA受体信号相关的丢失模型 肌张力障碍测试DA信号减弱，可能允许M4信号占优势，如何影响基础 神经节的输出和信号传递。在目标3中，我们将测试在基底节中如何以及在哪里与肌张力障碍相关的D1的丢失 DA受体信号导致运动缺陷，以及M4如何调节这些行为。