Regulation of synapse development by small GTPase cascades in Caenorhabditis elegans

秀丽隐杆线虫中小 GTP 酶级联对突触发育的调节

基本信息

批准号：
10735077
负责人：
Salvatore James Cherra
金额：
$ 40.65万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735077
关键词：
Actins Affect Alzheimer&apos s Disease Animals Binding Biochemistry Biological Assay Biological Models Biophysics Biosensor Brain Caenorhabditis elegans Cellular biology Complex Data Development Dominant-Negative Mutation Electron Microscopy Electrons Ensure Epilepsy F-Actin Fluorescence Microscopy Foundations Functional disorder Future GTPase-Activating Proteins Genetic Genetic Engineering Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Impairment In Vitro Intellectual functioning disability Knowledge Light Maintenance Measures Microfilaments Microscopic Mission Modeling Molecular Molecular Target Monomeric GTP-Binding Proteins Motor Motor Neurons Mutation Nervous System Nervous System Physiology Neurodegenerative Disorders Neurodevelopmental Disorder Neuromuscular Junction Neurons Neurophysiology - biologic function Neurosciences Organism Pathway interactions Pervasive Development Disorder Polymers Presynaptic Terminals Process Proteins Public Health Regulation Research Schizophrenia Series Signal Pathway Signal Transduction Signaling Protein Synapses Synaptic Vesicles United States National Institutes of Health autism spectrum disorder cholinergic cholinergic neuron cholinergic synapse disability improved in vitro Assay in vivo innovation insight light microscopy motor neuron development mutant nervous system development nervous system disorder neural circuit neuromuscular neuronal circuitry new therapeutic target novel therapeutics polymerization presynaptic prevent protein degradation protein protein interaction ras GTPase-Activating Proteins restoration synaptic function therapeutic development tool

项目摘要

Project Summary Synaptic development is a highly conserved process that underlies the functional connectivity of the nervous system. Deficits in synaptic development are associated with multiple neurological disorders, like autism spectrum disorders, intellectual disabilities, epilepsy, and schizophrenia. Therefore, restoration of healthy synapse development in cases of neurodevelopmental disorders represents one goal for developing better treatments. However, the lack of molecular targets to achieve this goal presents a significant barrier to the development of new therapies. Identifying the signaling pathways that promote or restore synapse development will reveal new mechanisms for modulating neuronal circuit development and function. The overall goal for the proposed research is to uncover how a series of small GTPases coordinate synapse development at the Caenorhabditis elegans neuromuscular junction. The central hypothesis is that PXF-1, a Rap guanine nucleotide exchange factor, promotes synapse development through the sequential activation of Rap, Ras, and Rac GTPases to sustain perisynaptic actin filaments during neuromuscular development. To identify the molecular mechanisms that govern the putative GTPase signaling cascade, we will use genetics and cell biology to identify the guanine nucleotide exchange factors and GTPase activating proteins that modulate each GTPase in the pathway. We will use fluorescent biosensors and genetic engineering to elucidate the molecular mechanisms through which Rap, Ras, and Rac signaling pathways interact with one another. The proposed research is innovative because it uses the powerful model system of Caenorhabditis elegans to study how GTPase networks function as molecular switches to control synapse development and motor circuit function. The development and use of new molecular tools to observe and modulate signal transduction in vivo will provide additional innovations for cellular and molecular neuroscience. The studies proposed in this application are significant because they will reveal how small G protein signaling networks promote synapse development and how modulation of these GTPase signaling modules can mitigate neuronal circuit dysfunctions.

项目摘要突触发展是一个高度保守的过程，它是神经的功能连通性的基础系统。突触发育中的缺陷与多种神经系统疾病有关，例如自闭症谱系障碍，智力障碍，癫痫和精神分裂症。因此，恢复健康神经发育障碍病例的突触发展是发展更好的目标治疗。但是，缺乏实现此目标的分子靶标的开发新疗法。识别促进或恢复突触发展的信号传导途径将揭示调节神经元电路发展和功能的新机制。总体目标拟议的研究是揭示一系列小型GTP酶如何协调突触的发展秀丽隐杆线虫神经肌肉连接。中心假设是PXF-1，RAP鸟嘌呤核苷酸交换因子，通过RAP，RAS和RAC的顺序激活促进突触的发展在神经肌肉发育过程中，GTPases维持周突触肌动蛋白丝。识别分子控制假定GTPase信号级联的机制，我们将使用遗传学和细胞生物学来识别鸟嘌呤核苷酸交换因子和GTPase激活蛋白质，这些蛋白质调节每个GTPase 路径。我们将使用荧光生物传感器和基因工程来阐明分子机制通过它，RAP，RAS和RAC信号通路相互作用。拟议的研究是创新性，因为它使用秀丽隐杆线虫的强大模型系统来研究GTPase网络如何功能充当分子开关，以控制突触发育和运动电路功能。发展和使用新分子工具观察和调节体内信号转导将提供其他创新用于细胞和分子神经科学。本应用中提出的研究很重要，因为它们将揭示小G蛋白信号网络如何促进突触的发展以及它们的调节方式 GTPase信号传导模块可以减轻神经元电路功能障碍。