Neuroimmunological insights into brain development and dysfunction: an integrative approach focused on microglial dynamics

对大脑发育和功能障碍的神经免疫学见解：专注于小胶质细胞动力学的综合方法

• 批准号: 10472831
• 负责人: Lucas M Cheadle
• 金额: $ 172.8万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472831
• 关键词: Address; Affect; American; Award; Biological; Biological Models; Brain; CRISPR screen; Cells; Child; Clinical; Communication; Complex; DNA Sequence Alteration; Development; Disease; Environmental Risk Factor; Female; Foundations; Functional disorder; Genetic; Genomics; Goals; Healthcare; Image; Immune; Immune system; Impairment; Individual; Intellectual functioning disability; Knowledge; Methods; Microglia; Molecular; Mus; Nature; Nervous system structure; Neurodevelopmental Disorder; Neurodevelopmental Problem; Neuroimmune; Persons; Pharmacology; Phase; Play; Population; Prevalence; Process; Research; Role; Sensory; Signal Transduction; Symptoms; Synapses; Therapeutic Intervention; Time; United States; United States National Institutes of Health; Viral; Visual; Work; autism spectrum disorder; awake; base; design; experience; high reward; high risk; immune activation; innovation; insight; male; mouse model; neural circuit; neuropathology; novel therapeutic intervention; postnatal; sex; tool; two-photon; virtual

Project Summary: Neurodevelopmental disorders such as autism and intellectual disability affect 14% of American children and over 50 million people world-wide. Pharmacological therapies for treating these disorders are virtually non- existent in large part due to our limited understanding of the neural circuit wiring deficits that underlie their diverse and nuanced symptoms. While it has been well-established that neurodevelopmental disorders emerge through a complex interplay of genetics (nature) and environmental factors (nurture), the majority of research into these conditions has focused on specific genetic mutations underlying rare subsets of disorders, leaving the environmental factors that affect a much wider array of these conditions poorly understood. To alleviate the suffering of as many individuals as possible, we will address this major gap in knowledge by defining the environmental factors that exacerbate neurodevelopmental dysfunction. Our approach is based upon mounting clinical and experimental evidence that impairments in interactions between the immune system and the brain drive neuropathology, an unexpected finding given that the immune and nervous systems were classically considered to be distinct biological domains. The central hypothesis underlying the proposed work is that a specialized class of brain-resident immune cells called microglia play a critical role in coordinating a late stage of circuit development that is thought to go awry in neuropathological states: the sensory experience-dependent refinement of developing synapses. If so, the disruption of microglial function in experience-dependent refinement may be a core feature of neurodevelopmental disorders rendering microglia a promising target for treatment, particularly because experience-dependent refinement represents a state of heightened plasticity when the brain may be particularly receptive to therapeutic intervention. Harnessing the unique advantages of the visual circuitry of the mouse as a model system, we will merge two-photon imaging of microglia and synapses in the brains of live, awake mice with single-cell genomics and CRISPR-based screens to define the roles of microglia in experience-dependent refinement. In parallel, we will utilize the maternal immune activation mouse model to identify specific mechanisms of refinement that are likely to be disrupted in neurodevelopmental disorders. Given that males are at least three times more likely to have autism than females, our work will also assess how these microglial processes differ depending upon sex. In the course of this work, we will develop much-needed viral tools for studying microglia in the brain. Our overarching goal is to lay the foundation for the development of new pharmacological strategies for treating neurodevelopmental disorders by restoring healthy microglial function during postnatal brain development. In addition to the high-risk/high-reward nature of the proposal, this project is particularly well-suited for the NIH Director’s New Innovator Award based upon conceptual novelty, promise to achieve key technological advances, and potential to alleviate a major healthcare burden affecting the United States and the world.

项目摘要： 自闭症和智力残疾等神经发育障碍会影响14％的美国儿童和 全球超过5000万人。治疗这些疾病的药理学疗法实际上不是 由于我们对神经电路布线的理解有限，因此存在很大程度上，这定义了潜水员的基础 和细微的符号。虽然已经确立了神经发育障碍的出现 遗传学（自然）和环境因素（培养）的复杂相互作用，大多数研究 条件集中在罕见的疾病子集的基本基因突变上，使 影响这些疾病的更广泛范围的环境因素理解不足。减轻 尽可能多的人的苦难，我们将通过定义来解决知识中的这一主要差距 加剧神经发育功能障碍的环境因素。我们的方法是基于安装 临床和实验证据表明免疫系统与大脑之间相互作用的损害 驱动神经病理学，这是一个意外的发现，鉴于免疫系统和神经系统是经典的 被认为是不同的生物领域。拟议工作的基础的核心假设是 称为小胶质细胞的专业类脑居民免疫核管在协调中起着至关重要的作用 被认为在神经病理状态下出现问题的电路开发：感官体验依赖性 发展突触的完善。如果是这样，在经验依赖性中的小胶质功能的破坏 细化可能是神经发育障碍的核心特征，使小胶质细胞成为有望的目标 治疗，特别是因为依赖经验的改进代表了可塑性的增强状态 当大脑特别接受治疗干预时。利用 小鼠作为模型系统的视觉电路，我们将合并小胶质细胞和突触的两光子成像 在现场的大脑中，具有单细胞基因组学和基于CRISPR的屏幕的清醒老鼠定义了角色 小胶质细胞在经验依赖性细化中。同时，我们将利用母体免疫激活小鼠 识别可能会在神经发育中破坏的精致特定机制的模型 疾病。鉴于男性患有自闭症的可能性是女性的三倍，我们的工作也将 评估这些小胶质过程如何根据性别而不同。在这项工作的过程中，我们将发展 急需研究大脑中小胶质细胞的病毒工具。我们的总体目标是为 通过恢复健康的神经发育障碍的新药物策略的制定 产后大脑发育过程中的小胶质功能。除了高风险/高回报的性质 提案，该项目特别适合NIH导演的新创新者奖。 概念新颖性，有望实现关键的技术进步以及减轻主要医疗保健的潜力 伯恩影响美国和世界。