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Axonal FMRP in Synaptic Development

突触发育中的轴突 FMRP

基本信息

批准号：
10672424
负责人：
Yuan Wang
金额：
$ 37.98万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672424
关键词：
Acute Adhesions Axon Axonal Transport Behavioral Brain Calcium Cell Adhesion Molecules Cells Chick Embryo Chickens Cues Development Elements Embryo Evolution Exocytosis FMR1 Fragile X Syndrome Functional Imaging Functional disorder Generations Glutamates Goals Human Image Impairment Inherited Intellectual functioning disability Knowledge Location Mammals Mediating Molecular Neurodevelopmental Disorder Outcome Pathway interactions Pharmaceutical Preparations Phenotype Physiological Presynaptic Terminals Probability Process Protein Deficiency Proteins Publishing RNA-Binding Proteins Regulation Resolution Role Synapses Synaptic Transmission Synaptic Vesicles Synaptic plasticity System Testing Time Traction Translations Up-Regulation Vesicle adhesion receptor autism spectrum disorder functional loss genetic approach genetic manipulation in vivo knockout animal neural circuit neuropathology neurotransmission neurotransmitter release novel novel therapeutics postsynaptic presynaptic presynaptic neurons prevent protein expression protein function sensor structural imaging synaptogenesis synaptotagmin therapeutic candidate therapy development

项目摘要

Project Summary This project will address the question of how abnormal synaptic development emerges in neurodevelopmental disorders. Our overall hypothesis is that disorganized synaptic adhesion and delayed functional assembly of synaptic vesicles (SVs) impair the formation and physiological maturation of presynaptic terminals, which triggers subsequent developmental deficits in synaptic connectivity and function. We will test this hypothesis in Fragile X syndrome (FXS), a leading inheritable form of autism and intellectual disability caused by functional loss of Fragile X mental retardation protein (FMRP). Experimental observations will utilize the evolutionally conserved endbulb terminals that are readily accessible for in vivo cell-autonomous characterizations in chicken embryos. We will pursue two specific aims to test several important hypotheses derived from our preliminary studies. · In Specific Aim 1, we will determine the role of FMRP-regulated synaptic adhesion in presynaptic terminal formation. We hypothesize that axonal FMRP promotes terminal formation, stabilization, and selective retraction through developmentally profiled synaptic adhesion. To test this hypothesis, we will use cell-group specific and temporally-controlled genetic manipulations combined with in vivo live imaging to identify the exact actions of FMRP-mediated axon transport vs. protein translation in dynamic terminal turnover. We will also identify FMRP-regulated synaptic adhesion elements in developing terminals and assess the effects of correcting these elements on FMRP loss-induced presynaptic and axon alterations. · In Specific Aim 2, we will determine the role of FMRP-regulated synaptotagmin (Syt) in functional maturation of presynaptic terminals. Syt1/2 are primary calcium sensors on SVs that trigger vesicle fusion and neurotransmitter release. We hypothesize that FMRP regulates presynaptic functional maturation by controlling the timely upregulation of Syt2 in nascent terminals. To test this hypothesis, we will determine the effects of expressing Syt2 on FMRP loss-induced deficits in SV activity, presynaptic protein machinery, and glutamate release. We will also determine the interplay between synaptic adhesion regulation and SV assembly under FMRP control using rescue studies. Together, these results will identify an origin of defective synaptic phenotypes, a hallmark of neurodevelopmental disorders. This knowledge is of vital importance because it will help establish a sensitive time window and identify novel therapeutic candidates for preventing, or at least reducing, the progress of synaptic deficits in FXS and other neurodevelopmental disorders.

项目概要该项目将解决神经发育过程中异常突触发育如何出现的问题失调。我们的总体假设是，突触粘附紊乱和功能组装延迟突触小泡（SV）损害突触前末梢的形成和生理成熟，从而触发随后突触连接和功能的发育缺陷。我们将在 Fragile X 中检验这个假设综合症（FXS），一种主要的遗传性自闭症和智力障碍，由大脑功能丧失引起脆性 X 智力迟钝蛋白 (FMRP)。实验观察将利用进化保守的端球端子可轻松用于鸡胚胎体内细胞自主表征。我们将追求两个具体目标来检验我们初步研究中得出的几个重要假设。 · 在具体目标 1 中，我们将确定 FMRP 调节的突触粘附在突触前的作用终端形成。我们假设轴突 FMRP 促进末端形成、稳定和通过发育特征突触粘附选择性回缩。为了检验这个假设，我们将使用细胞群特异性和时间控制的基因操作结合体内活体成像以识别动态中 FMRP 介导的轴突运输与蛋白质翻译的确切作用终端成交量。我们还将在开发过程中识别 FMRP 调节的突触粘附元件终端并评估纠正这些元素对 FMRP 丢失引起的突触前和轴突改变。 · 在具体目标 2 中，我们将确定 FMRP 调节的突触结合蛋白 (Syt) 在功能性中的作用突触前末梢的成熟。 Syt1/2 是 SV 上触发囊泡融合的主要钙传感器和神经递质释放。我们假设 FMRP 通过以下方式调节突触前功能成熟：控制新生终端中 Syt2 的及时上调。为了检验这个假设，我们将确定表达 Syt2 对 FMRP 丢失引起的 SV 活性、突触前蛋白缺陷的影响机械和谷氨酸释放。我们还将确定突触粘附之间的相互作用使用救援研究在 FMRP 控制下进行调节和 SV 组装。总之，这些结果将确定有缺陷的突触表型的起源，这是神经发育的标志失调。这些知识至关重要，因为它将有助于建立敏感的时间窗口并识别用于预防或至少减少 FXS 突触缺陷进展的新候选治疗药物其他神经发育障碍。