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

基本信息

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
项目类别：
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

项目摘要

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，经营一个跨学科和合作研究团队了解神经系统疾病的机制和新疗法。具体来说，我的兴趣在于了解不同来源的乙酰胆碱（ACh，即胆碱能）如何中间神经元与脚桥核）调节运动功能障碍，以及失衡的方式多巴胺 (DA) 和 M4 毒蕈碱乙酰胆碱受体 (mAChR) 信号传导会加剧运动功能障碍。我拥有深厚的生物化学和电生理学背景。我建议学习行为和伏安法完善我的培训的技术，并拥有制作高影响力出版物和的必要技能成功提交 R01。我获得了博士学位。 2015年4月，这是我获得K99/R00资格的最后一年。培训：除了 Conn 博士之外，我还有一个由行为药理学专家组成的咨询委员会，Dr. Conn 博士。 Jones，肌张力障碍和多巴胺能信号传导，Ehrlich 博士，以及使用分子探针了解 GPCR 发出信号，林兹利博士。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，我们在范德比尔特大学和外部确定了课程、研讨会、和会议，提供进一步的技术培训、演示经验、负责任的研究行为，以及过渡到独立所需的技能（报价谈判、任期、实验室管理等）。研究：抗 mAChR 疗法可有效减轻某些运动障碍的运动症状，但严重的副作用限制了它们的实用性。我们的实验室在阐明 mAChR 的作用方面取得了突破性进展，并且发现 M4 mAChR 亚型会减少 DA 释放、信号传导和相关运动行为。另外，M4 DA 信号传导的抑制在纹状体外部发生。这使我们得出这样的模型：当 DA 释放或信号传导低，这使得 M4 信号传导占主导地位，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 活性可能是 DA 和基底神经节活性的关键调节剂，提供与非选择性类似的功效 mAChRs没有副作用，这个还没有测试过。在初步数据中，我们报告了新工具的发现化合物直接检验我们的假设，证明失去 D1 DA 受体信号传导会降低基础神经节活动并产生运动缺陷，M4 活动双向调节运动缺陷。在目标 1 中，使用预测抗帕金森病功效的动物模型，我们将测试如何以及通过什么乙酰胆碱来源， M4 活动调节运动缺陷。在目标 2 中，我们将使用 D1 DA 受体信号传导缺失模型肌张力障碍，以测试 DA 信号传导减弱（可能使 M4 信号传导占主导地位）如何影响基础神经节输出和信号传导。在目标 3 中，我们将测试基底神经节肌张力障碍如何以及在何处与 D1 缺失相关 DA 受体信号传导导致运动缺陷，以及 M4 如何调节这些行为。