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.

项目总结