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Primary Cilia: A Novel Signaling Gateway To Neural Circuit Modulation

原发纤毛：神经回路调制的新型信号通路

基本信息

批准号：
10687260
负责人：
EVA S ANTON
金额：
$ 109.5万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-19 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687260
关键词：
Affect Animals Anosmia Apraxias Ataxia Axon Brain Bronchiectasis Cell Nucleus Cerebral cortex Cilia Collaborations Congenital Heart Defects Cystic kidney Defect Dendrites Development Developmental Delay Disorders Disease Epilepsy Face Genetic Genetic Transcription Goals Health Hepatic Cyst Human Image Infertility Intellectual functioning disability Knowledge Lead Live Birth Logic Maintenance Maps Microtubules Modeling Molecular Monitor Mood Disorders Neurodevelopmental Disorder Neurons Neurophysiology - biologic function Obesity Organ Organelles Organoids Outcome Pancreatic Cyst Pathway interactions Physiological Polydactyly Recovery of Function Research Retinal Degeneration Role Schizophrenia Sensory Services Shapes Signal Transduction Situs Inversus Technology Testing Therapeutic Time Work animation autism spectrum disorder brain malformation ciliopathy connectome design experimental study gene network genetic approach hearing impairment human model innovation insight multimodality nervous system disorder neural circuit neuronal circuitry neurotransmission novel novel therapeutics optical imaging optogenetics programs real-time images reconstruction repaired response tool transcriptomics transmission process

项目摘要

PROJECT SUMMARY Primary cilium, a microtubule based antennae-like organelle, is present in every cortical neuron, and when defective, leads to ciliopathies. A distinguishing feature of ciliopathies is defective neural circuit formation and function. Disrupted construction and function of neural circuits in ciliopathies lead to disorders such as autism, intellectual disabilities, mood disorders, obesity, and epilepsy, thus implying a role for primary cilia in neuronal function and circuit dynamics. Primary cilia signaling may serve as a nonsynaptic signaling mechanism through which environmental signals can shape and refine neuronal circuits in health and disease. Nonetheless, how primary cilia signaling sculpts neuronal circuit dynamics and whether primary cilia can be co-opted as a therapeutic conduit to mend neural circuit malfunctions remain enigmatic. We aim to resolve this challenge by defining the signaling mechanisms that are utilized by primary cilia to enable appropriate neuronal functions necessary for the emergence and maintenance of functional neural circuits in the brain. We will make this goal attainable by leveraging the latest advances in optogenetic and chemogenetic interrogation of signaling emanating from primary cilia, mapping neuronal ciliary receptome, profiling ciliary connectome within human cerebral cortical circuitry, live imaging cilia driven neuronal activity and transcriptional changes during neural circuit plasticity in living animals, and modeling human ciliopathies in brain organoids with the aim of rescuing circuit malfunctions using primary cilia as a tool. Collectively, this work will reveal how primary cilia activity is transformed into changes in neuronal circuit function and the pathways that must be successfully engaged to harness this insight in the service of ameliorating neural circuit disorders. These outcomes will offer a transformative opportunity to define new cellular principles of neural circuit formation and function and will open up new therapeutic avenues of neural circuit correction.

项目概要初级纤毛是一种基于微管的触角样细胞器，存在于每个皮质中神经元，当有缺陷时，会导致纤毛病。的一个显着特征纤毛病是神经回路形成和功能缺陷。施工中断纤毛病中的神经回路和功能会导致自闭症等疾病，智力障碍、情绪障碍、肥胖和癫痫，因此意味着初级纤毛在神经元功能和回路动力学中的作用。原发纤毛信号传导可能作为一种非突触信号传导机制，环境信号可以通过该机制塑造和完善健康和疾病中的神经元回路。尽管如此，初级纤毛如何信号传导塑造神经元回路动力学以及初级纤毛是否可以被增选作为修复神经回路故障的治疗渠道仍然是个谜。我们的目标通过定义所使用的信号机制来解决这一挑战初级纤毛能够实现出现和出现所需的适当的神经元功能维持大脑中的功能性神经回路。我们将实现这一目标通过利用光遗传学和化学遗传学审讯的最新进展初级纤毛发出的信号，映射神经元纤毛受体组，分析人类大脑皮层回路内的纤毛连接组，纤毛驱动的实时成像活体神经回路可塑性过程中的神经元活动和转录变化动物，并在大脑类器官中模拟人类纤毛病，目的是拯救使用初级纤毛作为工具的电路故障。总的来说，这项工作将揭示如何初级纤毛活动转化为神经元回路功能的变化必须成功利用这些途径才能利用这种洞察力来服务改善神经回路紊乱。这些成果将带来变革性的成果有机会定义神经回路形成和功能的新细胞原理并将开辟神经回路矫正的新治疗途径。