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

• 批准号: 10353430
• 负责人: BHOOMA ARAVAMUTHAN
• 金额: $ 18.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10353430
• 关键词: ARHGEF5 gene; Address; Adult; Affect; Agonist; Animals; Anti-Cholinergics; Award; Basal Ganglia; Brain; Cerebral Palsy; Child; Childhood; 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; 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; Sum; 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

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 这项提议将确定是否增加纹状体胆碱能中间神经元（ChI）的活动，在发展中国家， 小鼠脑可以预防新生儿脑损伤后的肌张力障碍 .新生儿肌张力障碍性脑瘫（CP） 脑损伤是儿童肌张力障碍的最常见原因 使人衰弱然而，其独特的病理生理学仍然研究不足。肌张力障碍的病理生理学更常见于 在以纹状体ChI超兴奋为特征的罕见遗传性肌张力障碍模型中进行了研究。然而，在这方面， 抗胆碱能药物通常对治疗CP的肌张力障碍无效。确定是否有纹状体 肌张力障碍性CP特异性的胆碱能病理学可以产生更好的靶向治疗。为此，我开发了 新生儿缺氧性脑损伤的临床相关啮齿类动物模型，其显示以下电生理标志物： 损伤后三周肌张力障碍，模拟新生儿脑损伤和肌张力障碍之间的临床潜伏期 出现。该潜伏期允许测试用于肌张力障碍预防的症状前干预。我 初步数据表明，在我的模型中，纹状体ChI数量增加，但年轻人的纹状体ChI兴奋 在症状前窗口期的小鼠可保护免于肌张力障碍。总之，这些数据表明， 纹状体ChI数量增加和纹状体ChI兴奋过度可能是 对肌张力障碍具有保护作用，因此可以增强以预防新生儿脑损伤后的肌张力障碍。 为了验证这一假设，我提出了以下目标：（1）确定纹状体的化学发生调节是否 新生儿脑损伤后幼年小鼠ChI活性改变成年小鼠肌张力障碍的严重程度;（2）确定 在年轻的、健康的小鼠中，纹状体ChI活性的化学遗传调节是否会引起肌张力障碍 （3）确定遗传性肌张力障碍中观察到的纹状体ChI超兴奋性是否也 存在于我的新生儿脑损伤后肌张力障碍模型中。这些研究将确定是否在 在新生儿脑损伤后持续增加纹状体ChI放电可以减少或预防肌张力障碍。 我的长期职业目标是经营一个专注于预防性治疗开发的转化研究实验室 治疗肌张力障碍性CP我研究基底神经节病理生理学已有十年，并开发了一种新的模型， 新生儿脑损伤后的肌张力障碍，其将用于所提出的实验。然而，为了完成 建议的研究和促进我的过渡到独立，我需要额外的指导培训切片 电生理学（Steve Mennerick博士）和化学遗传学（Jordan McCall博士）。作为我的医生兼科学家 顾问，乔尔Perlmutter博士将提供肌张力障碍病理生理学的专业知识，并确保翻译 我的研究的相关性。华盛顿大学医学院和神经病学系提供 一个世界知名的研究环境和热情和有效地支持初级教师的遗产。 总之，我提出的研究，导师团队，培训计划和制度环境为我铺平了道路， 独立性和提交关于 确定治疗目标 治疗肌张力障碍性CP