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.

项目总结： 自闭症和智力残疾等神经发育障碍影响着14%的美国儿童， 全世界有超过5000万人。治疗这些疾病的药物治疗实际上是非 其存在在很大程度上是由于我们对其多样性背后的神经回路连接缺陷的有限了解 和细微差别的症状。虽然众所周知，神经发育障碍是通过 遗传学(先天)和环境因素(后天)的复杂相互作用，大多数对这些因素的研究 条件集中在罕见疾病亚群潜在的特定基因突变上，留下了 环境因素对这些情况的影响范围更广，但人们对此知之甚少。为了缓解 为了让尽可能多的人遭受痛苦，我们将通过定义 加剧神经发育障碍的环境因素。我们的方法是基于安装 临床和实验证据表明，免疫系统和大脑之间相互作用的损害 驱动神经病理学，这是一个意想不到的发现，因为免疫和神经系统是经典的 被认为是不同的生物域。这项拟议的工作背后的中心假设是 一类特殊的大脑驻留免疫细胞，称为小胶质细胞，在协调晚期过程中发挥着关键作用 被认为在神经病理状态下出现错误的回路发育：感觉经验依赖性 完善发育中的突触。如果是这样的话，经验依赖的小胶质细胞功能的中断 精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成为 治疗，特别是因为依赖经验的改进代表了一种高度可塑性的状态 当大脑可能特别容易接受治疗干预的时候。利用其独特的优势 以小鼠的视觉回路为模型系统，我们将融合小胶质细胞和突触的双光子成像 在活着的清醒小鼠的大脑中，用单细胞基因组学和基于CRISPR的筛选来定义 小胶质细胞依赖于经验的精炼。同时，我们将利用母体免疫激活小鼠 识别神经发育中可能被破坏的特定精炼机制的模型 精神错乱。鉴于男性患自闭症的可能性至少是女性的三倍，我们的工作也将 评估这些小胶质细胞的突起如何根据性别的不同而不同。在这项工作中，我们将发展 研究大脑中的小胶质细胞急需的病毒工具。我们的首要目标是为 通过恢复健康来治疗神经发育障碍的新药物策略的开发 小胶质细胞在出生后脑发育过程中的功能。除了高风险/高回报的性质外， 建议，这个项目特别适合NIH主任的新创新者奖，基于 概念新颖性，实现关键技术进步的承诺，以及缓解重大医疗保健问题的潜力 影响美国和世界的负担。