Modulation of striatal cholinergic interneuron activity to prevent dystonic cerebral palsy

调节纹状体胆碱能中间神经元活动以预防肌张力障碍性脑瘫

基本信息

批准号：
10636773
负责人：
BHOOMA ARAVAMUTHAN
金额：
$ 18.64万
依托单位：
WASHINGTON UNIVERSITY
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：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636773
关键词：
ARHGEF5 gene Address Adult Affect Agonist Animals Anti-Cholinergics Award Basal Ganglia Brain Cerebral Palsy Child Childhood Cholinergic Agents Chronic Clinical Clozapine Corpus striatum structure Data Dopamine Dopamine D2 Receptor Dystonia Electrophysiology (science)Ensure Environment Exhibits Faculty Functional disorder Genetic Goals Grant Hypoxia Hypoxic Brain Damage Implant In Vitro Injections Injury Institution Interneurons Intervention Ischemia Jordan Life Ligands Live Birth Measures Mediating Medical Mentors Mentorship Modeling Motor Mus Neonatal Neonatal Brain Injury Neurology Neurons Oxides Pathology Pharmaceutical Preparations Physicians Pregnancy Prevention Preventive treatment Refractory Research Research Personnel Rodent Model Running Scientific Advances and Accomplishments Scientist Severities Slice Testing Therapeutic Training Translational Research Universities Viral Visual Washington career cholinergic clinically relevant designer receptors exclusively activated by designer drugs disability experimental study flu hypoxia neonatorum in vivo innovation medical schools mouse model multidisciplinary pediatric dystonia postnatal presymptomatic testing prevent response therapeutic target therapy development

项目摘要

PROJECT SUMMARY This proposal will determine whether increasing striatal cholinergic interneuron (ChI) activity in the developing mouse brain can prevent dystonia following neonatal brain injury . Dystonic cerebral palsy (CP) due to neonatal brain injury is the most common cause of childhood dystonia and is often medically refractory and functionally debilitating. Yet, its unique pathophysiology remains understudied. Dystonia pathophysiology is more commonly studied in models of rare genetic dystonias which are characterized by striatal ChI hyperexcitability. However, anticholinergic medications are often ineffective for treating dystonia in CP. Determining whether there is striatal cholinergic pathology specific to dystonic CP could yield better targeted treatments. To this end, I have developed a clinically-relevant rodent model of neonatal hypoxic brain injury that displays electrophysiologic markers of dystonia three weeks after injury, mimicking the clinical latency period between neonatal brain injury and dystonia emergence. This latency period allows testing of pre-symptomatic interventions for dystonia prevention. My preliminary data demonstrate increased striatal ChI number in my model but that striatal ChI excitation in young mice during the pre-symptomatic window may be protective against dystonia. In sum, these data suggest that increased striatal ChI number and striatal ChI hyperexcitability may be compensatory mechanisms that are protective against dystonia and, therefore, could be enhanced to prevent dystonia following neonatal brain injury. To test this hypothesis, I propose the following aims: (1) determine whether chemogenetic modulation of striatal ChI activity in young mice after neonatal brain injury changes dystonia severity in adult mice; (2) determine whether chemogenetic modulation of striatal ChI activity in young, otherwise healthy, mice can cause dystonia in adult mice; and (3) determine whether the striatal ChI hyperexcitability observed in genetic dystonias is also present in my model of dystonia following neonatal brain injury. These studies will determine whether pre- symptomatically increasing striatal ChI firing after neonatal brain injury could reduce or prevent dystonia. My long-term career goal is to run a translational research lab focused on preventative treatment development for dystonic CP. I have studied basal ganglia pathophysiology for ten years and have developed a new model of dystonia following neonatal brain injury which will be used for the proposed experiments. However, to complete the proposed research and facilitate my transition to independence, I need additional mentored training in slice electrophysiology (Dr. Steve Mennerick) and chemogenetics (Dr. Jordan McCall). As my physician-scientist advisor, Dr. Joel Perlmutter will provide expertise in dystonia pathophysiology and ensure the translational relevance of my research. The Washington University School of Medicine and Department of Neurology provide a world-renowned research environment and a legacy of passionately and effectively supporting junior faculty. In sum, my proposed research, mentorship team, training plan, and institutional environment pave my path to independence and submission of an R01 on identification of treatment targets for dystonic CP.

项目摘要该建议将确定在发育中是否增加了纹状体胆碱能中间神经元（CHI）活性新生儿脑损伤后，小鼠大脑可以预防肌张力障碍。由于新生儿而引起的肌张脑瘫（CP）脑损伤是儿童肌张力障碍的最常见原因，通常在医学上是难治性的，在功能上使人衰弱。然而，其独特的病理生理学仍在研究。肌张力障碍病理学更常见在稀有遗传性肌张力障碍的模型中进行了研究，这些模型的特征是纹状体卡过度刺激性。然而，抗胆碱能药物通常无法治疗CP中的肌张力障碍。确定是否有纹状体特定于肌张力障碍CP的胆碱能病理可以产生更好的靶向治疗方法。为此，我已经发展了新生儿低氧脑损伤的临床啮齿动物模型，该模型显示受伤后三周肌张力障碍，模仿新生儿脑损伤与肌张力障碍之间的临床潜伏期出现。该潜伏期允许测试预防肌张力障碍的症状前干预措施。我的初步数据表明，在我的模型中，纹状体CHI数量增加，但是Young中的纹状体CHI激发在症状前窗口期间的小鼠可以保护肌张力障碍。总而言之，这些数据表明纹状体卡数增加和纹状体CHI过度克服性可能是补偿机制防止肌张力障碍的保护作用，因此可以增强，以防止新生儿脑损伤后肌张力障碍。为了检验这一假设，我提出以下目的：（1）确定纹状体的化学发生调节是否新生儿脑损伤后年轻小鼠的CHI活性会改变成年小鼠的肌张力障碍严重程度；（2）确定年轻纹状体CHI活性的化学发生调节是否健康，小鼠会引起肌张力障碍在成年小鼠中；（3）确定在遗传肌张力纳斯中观察到的纹状体CHI过度兴奋性是否也是新生儿脑损伤后我的肌张力障碍模型中存在。这些研究将确定是否前新生儿脑损伤后有症状增加纹状体卡的发射可以减少或预防肌张力障碍。我的长期职业目标是运行一个专注于预防治疗开发的转化研究实验室用于肌张力障碍CP。我研究了基底神经节病理生理学已有十年了，并开发了一种新的模型新生儿脑损伤后的肌张力障碍将用于拟议的实验。但是，要完成拟议的研究并促进了我向独立的过渡，我需要在切片中进行其他指导的培训电生理学（Steve Mennerick博士）和化学遗传学（Jordan McCall博士）。作为我的医师科学家顾问Joel Perlmutter博士将提供肌张力障碍病理生理学专业知识，并确保翻译我的研究的相关性。华盛顿大学医学院和神经科提供一个世界知名的研究环境，以及热情有效地支持初级教师的遗产。总而言之，我提议的研究，指导团队，培训计划和机构环境为我的道路铺平了道路独立和提交R01 识别治疗目标用于肌张力障碍CP。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Role of Child Neurologists in the Management of Motor Disability in Cerebral Palsy: Establishing the Path Forward.

儿童神经科医生在脑瘫运动障碍管理中的作用：建立前进的道路。

DOI：
10.1016/j.pediatrneurol.2023.03.018
发表时间：
2023
期刊：
Pediatric neurology
影响因子：
3.8
作者：
Gelineau-Morel,Rose;Kim,Young-Min;O'Malley,JenniferA;Wilson,JennyL;Aravamuthan,BhoomaR
通讯作者：
Aravamuthan,BhoomaR

Uncertainties regarding cerebral palsy diagnosis: opportunities to operationalize the consensus definition.

脑瘫诊断的不确定性：实施共识定义的机会。

DOI：
10.1101/2023.06.29.23292028
发表时间：
2023
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Aravamuthan,BhoomaR;Fehlings,DarcyL;Novak,Iona;Gross,Paul;Alyasiri,Noor;Tilton,Ann;Shevell,Michael;Fahey,Michael;Kruer,Michael
通讯作者：
Kruer,Michael

Cerebral Palsy in Child Neurology and Neurodevelopmental Disabilities Training: An Unmet Need.

DOI：
10.1177/08830738211072711
发表时间：
2022-03
期刊：
Journal of child neurology
影响因子：
1.9
作者：
通讯作者：

Mice born preterm develop gait dystonia and reduced cortical parvalbumin immunoreactivity.

早产小鼠出现步态肌张力障碍并降低皮质小白蛋白免疫反应性。

DOI：
10.1101/2024.02.01.578353
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Gemperli,Kat;Folorunso,Femi;Norin,Benjamin;Joshua,Rebecca;Hill,Clayton;Rykowski,Rachel;Galindo,Rafael;Aravamuthan,BhoomaR
通讯作者：
Aravamuthan,BhoomaR

A Broader Perspective on Motor Rehabilitation Guidelines for Cerebral Palsy.

脑瘫运动康复指南的更广泛视角。