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.

项目摘要该项目将解决神经发育中如何出现异常突触发育的问题疾病。我们的总体假设是，混乱的合成粘合剂和延迟功能组装突触蔬菜（SVS）损害了突触前终端的形成和物理成熟，这会触发随后的发展定义了突触连通性和功能。我们将在脆弱的x中检验这一假设综合征（FXS），一种自闭症和智力残疾的领先形式，由功能丧失引起脆弱的X智障蛋白（FMRP）。实验观察将利用进化保守的鸡蛋中体内细胞自主特征很容易访问的末端终端。我们将追求两个具体的目标，以检验从我们的初步研究中得出的几个重要假设。在特定目标1中，我们将确定FMRP调节的突触粘合剂在突触前的作用终端形成。我们假设轴突FMRP促进了末端形成，稳定和通过开发的突触粘合剂进行选择性缩回。为了检验这一假设，我们将使用特定细胞组的特定和暂时控制的遗传操作与体内活体结合成像以确定FMRP介导的轴突转运与动态中蛋白质翻译的确切作用终端营业额。我们还将在开发中确定FMRP调节的突触胶元素终端并评估纠正这些元素对FMRP损失引起的突触前和轴突改变。在特定的目标2中，我们将确定FMRP调节的突触量（SYT）在功能中的作用突触前末端的成熟。 SYT1/2是触发囊泡融合的SV上的主要钙传感器和神经递质释放。我们假设FMRP通过控制新生末端中SYT2的及时上调。为了检验这一假设，我们将确定表达SYT2对FMRP损失引起的SV活性缺陷的影响，突触前蛋白机械和谷氨酸释放。我们还将确定合成粘合剂之间的相互作用使用救援研究在FMRP控制下调节和SV组装。这些结果将共同确定有缺陷的突触表型的起源，这是神经发育的标志疾病。这些知识至关重要，因为它将有助于建立一个敏感的时间窗口并确定新颖的治疗候选者用于预防或至少减少FXS突触缺陷的进展其他神经发育障碍。