Adhesion-GPCRs: Regulators of dendritic development, synaptogenesis and mental health

粘附-GPCR：树突发育、突触发生和心理健康的调节因子

基本信息

批准号：
9311432
负责人：
Kimberly R Tolias
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-08 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311432
关键词：
Adhesions Affect Alzheimer&apos s Disease Angiogenesis Inhibitors BAI1 gene BAI2 gene BAI3 gene Biochemistry Biological Assay Biology Bipolar Disorder Bipolar I Brain Brain Diseases Cell Surface Receptors Characteristics Chromosome Mapping Cognition Disorders Complex Copy Number Polymorphism Coupling Data Dendrites Dendritic Spines Development Disease Electrophysiology (science)Equilibrium Excitatory Synapse Exhibits Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genetic Models Germ-Line Mutation Goals Growth Heterogeneity Hippocampus (Brain)Hot Spot Human Image Intellectual functioning disability Knowledge Lead Ligand Binding Link Measures Mediating Mental Depression Mental Health Microtubules Modality Modeling Molecular Molecular Conformation Monomeric GTP-Binding Proteins Mood Disorders Neurons Pathway interactions Patients Phase Physiological Play Process Property Proteins Psyche structure Publishing Regulation Reporter Research Resistance Rett Syndrome Role Schizophrenia Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Single Nucleotide Polymorphism Structure Synapses Syndrome Testing Time Translating Validation Vertebral column age related autism spectrum disorder base extracellular growth promoting activity human disease in vivo inhibitor/antagonist insight interdisciplinary approach neural circuit neurodevelopment neuroligin 1 neuron development new therapeutic target novel response rho rho GTP-Binding Proteins spatiotemporal success synaptic function synaptogenesis

项目摘要

PROJECT SUMMARY Dendrites exhibit immense diversity in their macrostructure (arbors), which stipulates the availability of a neuron to circuits and its computational properties, and microstructure (dendritic spines), which dynamically support and shape synaptic function. Arbor and spine/synapse development must be coordinated to form functional dendrites. Though synaptic activity plays a crucial role, the heterogeneity of developmental responses to activity indicates that other mechanisms are required. In this proposal, we will test the hypothesis that the adhesion G-protein coupled receptor (A-GPCR) brain-specific angiogenesis inhibitor 1 (BAI1/ ADGRB1) coordinates dendritic arbor and spine development through differential activation of multiple signaling pathways. This hypothesis is based on our published and preliminary data showing: (i) that BAI1 mediates growth arrest of dendritic arbors via a novel pathway coupling to the Rho-family small GTPase RhoA; (ii) that BAI1 promotes excitatory synaptogenesis in cortical and hippocampal neurons via the Rho-family small GTPase Rac1 and trans-synaptic signaling; and (iii) that BAI1 differentially affects dendrite development in an age-dependent manner and that altering BAI1 configuration has age-dependent effects on downstream signaling pathways. We propose a multidisciplinary approach to define the roles of BAI A-GPCRs in regulating and coordinating dendritic arbor and spine/synapse development utilizing in vivo and cultured neurons, genetic models, molecular replacement, live imaging with fluorescent reporters, mixed culture assays, biochemistry and electrophysiology. The pathways that we are defining include proteins implicated in treatment-resistant bipolar disorder (Bcr), autism spectrum disorder (neuroligin-1 and IRSp53), and schizophrenia (BAI3). Thus, success of this proposal will not only provide material advances in the study of dendrite development and synaptogenesis, but also test a novel and powerful hypothesis regarding the coordination of these processes and provide new therapeutic targets against widespread human mental diseases.

项目摘要树突在其宏观结构（Arbors）中表现出巨大的多样性，这规定了A的可用性神经元到电路及其计算特性和微观结构（树突状刺），该动态动态支持和形状突触功能。轴和脊柱/突触的发育必须协调以形成功能性树突。尽管突触活动起着至关重要的作用，但发育的异质性对活动的反应表明需要其他机制。在此提案中，我们将检验假设粘附G蛋白偶联受体（A-GPCR）脑特异性血管生成抑制剂1（BAI1/ ADGRB1）通过差异激活多种信号通路。该假设基于我们发布的和初步的数据：（i）bai1 通过与Rho-family小型GTPase Rhoa耦合的新型途径介导树突状乔木的生长停滞；（ii）BAI1通过Rho-family small促进皮质和海马神经元中的兴奋性突触发生 GTPase Rac1和反式突触信号传导；（iii）BAI1在某个与年龄有关的方式和改变BAI1配置对下游具有年龄依赖性影响信号通路。我们提出了一种多学科的方法来定义BAI A-GPCR在调节中的作用以及使用体内和培养的神经元中的树突状乔木和脊柱/突触的发展，遗传模型，分子替代品，荧光记者的实时成像，混合培养测定，生物化学和电生理学。我们定义的途径包括与治疗抗药性有关的蛋白质躁郁症（BCR），自闭症谱系障碍（Neuroligin-1和IRSP53）和精神分裂症（BAI3）。因此，该提案的成功不仅将在树突开发研究和突触发生，但还检验了有关这些过程协调的新颖而有力的假设并为广泛的人类精神疾病提供新的治疗靶标。