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: 10336602
• 负责人: Mark S Moehle
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10336602
• 关键词: Acetylcholine; Adverse effects; Advisory Committees; Anatomy; Animal Model; Antiparkinson Agents; Basal Ganglia; Behavior; Behavioral; Biochemical; Biochemistry; Cell Nucleus; Cells; Corpus striatum structure; Coupling; Cyclic AMP; 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 therapeutic intervention; 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调查员，经营跨学科和 合作研究团队了解神经系统疾病的机制和新型治疗方法。 具体而言，我的兴趣围绕着了解不同的乙酰胆碱来源（ACH，即胆碱能 中间神经元诗句核核核）调节运动功能障碍，以及如何失衡 多巴胺（DA）和M4毒蕈碱乙酰胆碱受体（MACHR）信号传导加剧运动功能障碍。我 具有强大的生物化学和电生理学背景。我建议学习行为和伏安法 解决我的培训的技术，并具有生产高影响力出版物的必要技能和 成功的R01提交。我获得了博士学位2015年4月，这是我获得K99/R00的最后一年。 培训：除了Conn博士外，我还有一个行为药理学专家咨询委员会，博士。 琼斯，肌张力障碍和多巴胺能信号传导，Ehrlich博士，以及使用分子探针来了解GPCR 信号，Lindsley博士。该委员会将提供必要的培训和指导来实现这一目标 提议。在委员会之外，我们在范德比尔特和外部都确定了课程，研讨会， 和会议，以提供进一步的技术培训，演示经验，负责任的研究行为， 以及必要的技能（提供谈判，任期，实验室管理等），以过渡到独立性。 研究：抗MACHR疗法可有效减少某些运动障碍的运动症状，但 严重的副作用限制了它们的效用。我们的实验室已经取得了突破，阐明了Machrs的角色，并 发现M4 MACHR亚型减少了DA释放，信号传导和相关的运动行为。另外，M4 DA信号的抑制作用在纹状体外进行了音调发生。这使我们了解了当DA时 释放或信号很低，这允许M4信号占主导地位，导致运动功能障碍，并导致 我们的广泛假设是M4拮抗剂将减少运动障碍中的运动缺陷。而M4 活动可能是DA和基底神经节活动的关键调节剂，提供与非选择性相似的功效 没有副作用的MACHR，尚未对此进行测试。在初步数据中，我们报告了新颖工具的发现 化合物直接检验我们的假设，证明失去D1 DA受体信号传导减少了基础 神经节活动并产生运动缺陷，M4活性双向调节运动缺陷。在AIM 1中， 使用预测抗帕金森氏疗效的动物模型，我们将测试如何以及通过什么ACH来源， M4活动调节运动缺陷。在AIM 2中，我们将使用与D1 DA受体信号丢失的模型 肌张力障碍测试DA信号传导如何降低，可能允许M4信号占主导地位，影响基础 神经节输出和信号传导。在AIM 3中，我们将测试基底神经节肌张力障碍与D1的损失联系在一起的方式和地点 DA受体信号传导导致运动缺陷，以及M4如何调节这些行为。