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.

项目摘要 星形胶质细胞形态成熟是健康中枢神经系统发育的关键步骤。不成熟 星形胶质细胞详细介绍了它们的过程，并用细，末端的传单过程渗入神经胶质。这些 过程允许与邻近星形胶质细胞的细胞电池通信，脉管系统和 包装突触，星形胶质细胞参与神经递质的吸收，突触发展和 稳定。星形胶质细胞形态发生与神经元成熟和突触发生相吻合，暗示 这两个事件之间的共同机制。脑衍生的神经营养因子（BDNF）是一种发育 分子对于神经元中的发育和活性依赖性可塑性至关重要。我们的实验室表明BDNF 通过TRKB受体同工型（TRKB.T1）与星形胶质细胞相互作用，以促进星形胶质细胞形态学 成熟。我们发表的工作表明TRKB.T1的星形胶质细胞删除导致25％的降低 星形胶质细胞体积和分支复杂性，这种变化持续到成年。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连锁的NDD，RETT综合征（RTT）。初步证据表明RTT中的星形胶质细胞 小鼠模型的体积缺陷类似于TRKB.T1敲除，并且基因表达失调。 报告表明，trkb.t1同工型与小的rhogtpase抑制剂相互作用，尽管它 功能意义相对较未知。我们建议评估星形胶质细胞Rhogtpase信号传导和 响应BDNF的细胞骨架动力学和潜在的治疗性TRKB激活剂利用体外 以及原位遗传，分子和成像技术。此外，我们将评估TRKB治疗剂是否 救助RTT星形胶质细胞形态缺陷和基因失调。我的具体目的是（1）确定 TRKB.T1激活的信号传导后果和（2）TRKB.T1激活对形态学变化的作用 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的发现。 该建议符合大脑的优先级，启动了（1）证明关系因果关系的2.0和（2） 识别可观察到的大脑特性的基本原理。