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Unraveling the Dynamic Role of Purkinje Cell Neurotransmission in Neurodevelopment.

揭示浦肯野细胞神经传递在神经发育中的动态作用。

基本信息

批准号：
10191576
负责人：
Jason Singh Gill
金额：
$ 19.11万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10191576
关键词：
Address Affect Affective Age Anatomy Animal Behavior Animal Model Behavior Behavioral Behavioral Assay Biological Assay Brain Brain Injuries Cell physiology Cells Cerebellar Cortex Cerebellar Diseases Cerebellar Nuclei Cerebellum Childhood Clinical Cognitive Data Development Diagnosis Disease Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Etiology Exposure to Family Funding Genetic Genetic Models Grooming Human Image Imaging Techniques Immunohistochemistry Incidence Inferior Injury Instinct Intervention Leadership Life Marble Mediating Medicine Mendelian disorder Mentors Mentorship Modeling Morbidity - disease rate Mus Neurodevelopmental Disability Neurodevelopmental Disorder Neurologic Neurologist Neurons Neurophysiology - biologic function Neurosciences Nose Nuclear Olives - dietary Outcome Output Pathogenesis Pathology Pathway Analysis Patients Pattern Pediatric Hospitals Pediatric Neurology Personal Satisfaction Physicians Physiological Population Pregnancy Prevention Preventive measure Property Public Health Purkinje Cells Research Research Institute Role Scientist Site Structure System Techniques Testing Tetracyclines Texas Therapeutic Third Pregnancy Trimester Training Transcriptional Activation United States National Institutes of Health Work analytical tool base behavioral outcome burden of illness career cohesion cohort college critical developmental period critical period design disability leave disorder prevention experience experimental study field study genetic manipulation genome editing in vivo innovation insight motor behavior motor deficit mouse development mouse genetics network dysfunction neurodevelopment neurotransmission postnatal premature prevent preventive intervention research facility response safety net social societal costs support network vesicular GABA transporter water maze

项目摘要

Neurodevelopmental disability arising from prematurity poses a large and increasing disease burden and has increasingly been associated with cerebellar pathogenesis. Cerebellar development coincides with a critical developmental period during which establishment of brain networks supports neurotypical outcomes. However, the precise role of the cerebellum in supporting network structure and function through early development is poorly understood. Developing interventions to prevent and treat neurodevelopmental disability associated with associated with prematurity requires a comprehensive understanding of the dynamic circuit response to functional perturbations. This proposal uses unique features of mouse development in combination with the sophistication of mouse genetic manipulations to dynamically alter cerebellar function through a critical developmental window while comprehensively characterizing the resulting anatomic, physiologic, and behavioral disruptions of the associated networks. The central hypothesis of this proposal is that cerebellar function is first required for structural establishment of brain networks while subsequently being important for ongoing function, a dynamic that underlies the spectrum of neurodevelopmental disability. This proposal will take advantage of a model for inducible silencing of Purkinje cell neurotransmission developed by the candidate. In Aim 1, the experiments will test how early vs late cerebellar disruption affects behavior, predicting that early silencing will have pervasive behavioral deficits while late silencing will produce domain specific functional deficits. In Aim 2, the experiments are designed to examine how early vs late silencing affects the assembly and function of brain circuits using anatomic and electrophysiologic analyses. With these aims, the proposal outlines a rigorous approach that combines dynamic genetic perturbations, quantitative anatomic and electrophysiologic analyses, and cross-domain behavioral assays to better understand how early cerebellar insult contributes to neurodevelopmental disability. The candidate is a trained pediatric neurologist with extensive clinical exposure to diagnosis and treatment of neurodevelopmental disorders, application and analysis of basic and advanced imaging techniques, and research experience in model organism behavioral assays. This proposal is mentored by Dr. Roy Sillitoe, a leader in cerebellar neuroscience who has strong track record of NIH funding, mentorship, and scientific leadership. All experiments will be conducted at the Neurologic Research Institute, a pediatric neurology research facility that draws on the clinical excellence of Texas Children’s Hospital and the world-class neuroscience of Baylor College of Medicine. The professional development and training plan is designed to poise the candidate for a career as a physician scientist focused on the prevention and treatment of neurodevelopmental disability in the pediatric population specifically utilizing a gap based approach that incorporates training in network analysis and advanced statistical techniques. The completion of the entailed aims will elucidate the mechanisms by which cerebellar disruptions contribute to neurodevelopmental disability.

早产引起的神经发育障碍造成了巨大且不断增加的疾病负担，越来越多地与小脑发病机制相关。小脑的发育与关键的发育同时发生大脑网络的建立支持神经典型结果的发育时期。然而，小脑在早期发育过程中支持网络结构和功能的确切作用是不太了解。制定干预措施来预防和治疗与以下疾病相关的神经发育障碍与早产相关的需要全面了解动态电路响应功能扰动。该提案结合了鼠标开发的独特功能复杂的小鼠基因操作通过关键的动态改变小脑功能发育窗口，同时全面表征由此产生的解剖学、生理学和行为学特征相关网络的中断。该提案的中心假设是小脑功能首先大脑网络结构建立所必需的，同时对于持续的功能也很重要，神经发育障碍的动态变化。该提案将利用候选人开发的浦肯野细胞神经传递诱导沉默模型。在目标 1 中，实验将测试早期和晚期小脑干扰如何影响行为，预测早期沉默会影响行为。具有普遍的行为缺陷，而晚期沉默将产生特定领域的功能缺陷。在目标 2 中，这些实验旨在研究早期沉默与晚期沉默如何影响大脑的组装和功能使用解剖学和电生理学分析的电路。为了实现这些目标，该提案概述了严格的结合动态遗传扰动、定量解剖学和电生理学分析的方法，和跨领域行为分析，以更好地了解早期小脑损伤如何导致神经发育障碍。候选人是一位训练有素的儿科神经科医生，具有广泛的临床经验神经发育障碍的诊断和治疗，基础和高级的应用和分析成像技术以及模型生物行为测定的研究经验。此提案已得到指导作者：Roy Sillitoe 博士，小脑神经科学领域的领军人物，在 NIH 资助、指导、和科学领导。所有实验将在儿科神经学研究所进行神经病学研究机构借鉴了德克萨斯儿童医院的临床卓越性和世界一流的水平贝勒医学院神经科学。专业发展和培训计划旨在平衡从事医学科学家职业的候选人，专注于预防和治疗儿科人群的神经发育障碍，特别是利用基于间隙的方法包含网络分析和高级统计技术的培训。完成所蕴含的目标将阐明小脑干扰导致神经发育障碍的机制。