BDNF signaling via astrocyte Trkb.T1 drives morphogenesis and maturation of astrocytes, a dysregulated feature of Rett syndrome

通过星形胶质细胞 Trkb.T1 的 BDNF 信号传导驱动星形胶质细胞的形态发生和成熟，这是雷特综合征的失调特征

• 批准号: 10488059
• 负责人: Raymundo Daniel Hernandez
• 金额: $ 4.19万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-10 至 2023-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488059
• 关键词: Actins; Adult; Affect; Affinity; Animals; Astrocytes; Award; Biological Assay; Biology; Brain; Brain-Derived Neurotrophic Factor; Cell Communication; Cell physiology; Cells; Cellular Structures; Coculture Techniques; Complex; Cytoskeletal Modeling; Data Analyses; Development; Developmental Gene; Disease; Disease model; Doctor of Philosophy; Doctor' s Degree; Electrophysiology (science); Etiology; Event; Fluorescence; Functional disorder; Gene Expression; Genes; Genetic; Goals; Health; Homeostasis; Imaging Techniques; In Situ; In Vitro; Intervention; Knock-out; Knockout Mice; Link; Maintenance; Measures; Medicine; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Neurobiology; Monitor; Morphogenesis; Morphology; Mus; Neuraxis; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neuropil; Neurosciences; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathologic; Pathway interactions; Pharmacology; Phase; Preparation; Principal Investigator; Process; Property; Protein Isoforms; Proteins; Publications; Publishing; Receptor Activation; Receptor Signaling; Reporting; Research; Research Project Grants; Rett Syndrome; Role; Signal Transduction; Structure; Supporting Cell; Synapses; Testing; Therapeutic; Training Programs; Universities; Viral; Work; base; career; cell type; confocal imaging; design; experience; experimental study; imaging modality; in vivo imaging; inhibitor; interest; live cell imaging; molecular imaging; mouse model; nervous system development; neuronal growth; neurotransmitter uptake; neurotrophic factor; novel; optogenetics; postnatal; pre-doctoral; presynaptic; professor; programs; response; response to injury; rhoB p20 GDI; synaptogenesis; targeted treatment; tenure track; therapeutic target; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Astrocyte morphological maturation is a critical step for healthy central nervous system development. Immature astrocytes elaborate their processes and infiltrate the neuropil with fine, terminal, leaflet processes. These processes allow for cell-cell communication with neighboring astrocytes, ensheathment of the vasculature and enwrapping synapses, and where astrocytes participate in neurotransmitter uptake, synapse development and stabilization. Astrocyte morphogenesis coincides with neuronal maturation and synaptogenesis, implicating a common mechanism between these two events. Brain-derived neurotrophic factor (BDNF) is one developmental molecule crucial for development and activity-dependent plasticity in neurons. Our lab has shown that BDNF interacts with astrocytes through a TrkB receptor isoform (TrkB.T1) to promote astrocyte morphological maturation. Our published work demonstrates astrocyte deletion of TrkB.T1 results in a 25% reduction in astrocyte volume and branching complexity, a change that persists through adulthood. Our discovery is relevant to health, as neurodevelopmental disorders (NDDs) are associated with BDNF dysregulation, including the X-linked NDD, Rett Syndrome (RTT). Preliminary evidence demonstrates that astrocytes in RTT mouse models have volume deficits similar to TrKB.T1 knockout accompanied by dysregulated gene expression. Reports demonstrate that the TrkB.T1 isoform uniquely interacts with a small RhoGTPase inhibitor, though its functional significance is relatively unknown. We propose to evaluate astrocyte RhoGTPase signaling and cytoskeletal dynamics in response to BDNF and potentially therapeutic TrkB activators utilizing in vitro and in situ genetic, molecular, and imaging techniques. Furthermore, we will assess if TrkB therapeutics rescue RTT astrocyte morphology deficits and gene dysregulation. My specific aims seek to (1) determine signaling consequences of TrkB.T1 activation and (2) the role of TrkB.T1 activation on morphological change in astrocytes as well as to expand upon our discovery by (3) evaluating astrocyte TrkB.T1 in a relevant NDD model. This proposal meets the priorities of the BRAIN Initiate 2.0 of (1) demonstrating causality of relationships and (2) identifying fundamental principles of observable brain properties.

项目概要 星形胶质细胞形态成熟是中枢神经系统健康发育的关键步骤。不成熟 星形胶质细胞精心设计它们的突起，并通过精细的、末端的、小叶的突起浸润神经纤维。这些 该过程允许细胞与邻近的星形胶质细胞进行通信，形成脉管系统和 包裹突触，星形胶质细胞参与神经递质摄取、突触发育和 稳定。星形胶质细胞形态发生与神经元成熟和突触发生同时发生，这意味着 这两个事件之间的共同机制。脑源性神经营养因子（BDNF）是一种发育因子 对神经元发育和活动依赖性可塑性至关重要的分子。我们的实验室已经证明 BDNF 通过 TrkB 受体亚型 (TrkB.T1) 与星形胶质细胞相互作用，促进星形胶质细胞形态 成熟。我们发表的工作表明，星形胶质细胞删除 TrkB.T1 会导致星形胶质细胞减少 25% 星形胶质细胞体积和分支复杂性，这种变化会持续到成年期。我们的发现是 与健康相关，因为神经发育障碍 (NDD) 与 BDNF 失调有关， 包括 X 连锁 NDD、Rett 综合征 (RTT)。初步证据表明，RTT 中的星形胶质细胞 小鼠模型具有类似于 TrKB.T1 敲除的体积缺陷，并伴有基因表达失调。 报告表明，TrkB.T1 同工型与小型 RhoGTPase 抑制剂具有独特的相互作用，尽管其 功能意义相对未知。我们建议评估星形胶质细胞 RhoGTPase 信号传导和 利用体外对 BDNF 和潜在治疗性 TrkB 激活剂的细胞骨架动力学反应 以及原位遗传、分子和成像技术。此外，我们将评估 TrkB 疗法是否 挽救 RTT 星形胶质细胞形态缺陷和基因失调。我的具体目标是 (1) 确定 TrkB.T1 激活的信号后果以及 (2) TrkB.T1 激活对形态变化的作用 星形胶质细胞以及通过 (3) 在相关 NDD 模型中评估星形胶质细胞 TrkB.T1 来扩展我们的发现。 该提案符合 BRAIN Initiate 2.0 的优先事项：(1) 证明关系的因果关系，以及 (2) 识别可观察的大脑特性的基本原理。