Investigating the Role of cnb-1 and chpf-1 in GABA DD Motor Neuron Remodeling and Synapse Maintenance

研究 cnb-1 和 chpf-1 在 GABA DD 运动神经元重塑和突触维持中的作用

基本信息

批准号：
10680262
负责人：
Sam Liu
金额：
$ 3.5万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2023-03-21 至 2026-03-20
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680262
关键词：
Adolescent Adult Affect Animals Architecture Axon Birth Brain Caenorhabditis elegans Calcineurin Calcium Calcium Signaling Calcium-Binding Domain Catalytic Domain Cells Cholinergic Receptors Clustered Regularly Interspaced Short Palindromic Repeats Development Dorsal EF Hand Motifs Engineering Future Gene Targeting Genes Genetic Genetic Transcription Goals Homeostasis Human Image Intestines Invertebrates Label Link Maintenance Masks Modeling Molecular Motor Neurons Muscle Mutation Nematoda Nervous System Neuroglia Neurons Operon Pathway interactions Phylogeny Postembryonic Presynaptic Terminals Process Proteasome Inhibitor Proteins Regulation Role Schizophrenia Site Supine Position Synapses Synaptic Receptors Taxes Techniques Tissues Transcriptional Regulation Whole Organism Work autism spectrum disorder calcineurin phosphatase experimental study gamma-Aminobutyric Acid homeodomain loss of function multicatalytic endopeptidase complex mutant nervous system disorder neural circuit null mutation postsynaptic transcription factor transcriptome sequencing

项目摘要

Project Summary During development of the human brain, synaptic connections undergo intensive rewiring in order to form mature circuits. Disruption of developmental remodeling in humans is linked to neurological disorders such as schizophrenia and autism spectrum disorders. The goal of this project is to identify conserved mechanisms that direct synapse remodeling. The ease of genetics, couple with the simpler organization and invariant architecture of invertebrate nervous systems offer strong advantages for studies of neuronal remodeling. My work focuses on the remodeling of GABAergic dorsal D-class (DD) motor neurons in the nemaode Caenorhabditis elegans. Prior studies have largely focused on the remodeling of presynaptic terminals. In contrast, my preliminary work has focused on understanding mechanisms that direct the elimination of postsynaptic receptors during remodeling. post-synaptic domain. The Francis lab previously demonstrated that the homeodomain transcription factor dve-1 is required for synapse elimination in GABA neurons. My work focuses on two putative DVE-1 targets, the calcineurin-like EF-hand protein CHP1/chpf-1 and the regulatory subunit of CalciNeurin PPP3R1/cnb-1, that were shown to be downregulated in dve-1 mutants. My preliminary studies suggest that mutation of either cnb-1 or chpf-1 disrupt synapse elimination during remodeling. My proposed work will determine the functional requirement and site of action for cnb-1, and identify the contribution of calcineurin phosphatase and proteasomal function to synapse elimination (Aim 1). In Aim 2, I will define how chpf-1 contributes to synapse elimination and maintenance. In Aim 3, I will identify additional potential targets of dve-1 in the remodeling pathway by using neuron-specific RNA-seq. My proposed work will advance our understanding of remodeling and the mechanisms of regulation, potentially providing targets for future exploration.

项目概要在人脑的发育过程中，突触连接经历密集的重新布线以形成成熟的电路。人类发育重塑的破坏与神经系统疾病有关，例如精神分裂症和自闭症谱系障碍。该项目的目标是确定保守机制直接突触重塑。遗传学的简单性，加上更简单的组织和不变性无脊椎动物神经系统的结构为神经元重塑的研究提供了强大的优势。我的工作重点是线虫 GABA 能背 D 类 (DD) 运动神经元的重塑秀丽隐杆线虫。先前的研究主要集中在突触前末梢的重塑。在相比之下，我的初步工作侧重于理解指导消除的机制重塑过程中的突触后受体。突触后域。弗朗西斯实验室此前证明 GABA 神经元中的突触消除需要同源域转录因子 dve-1。我的工作重点关注两个假定的 DVE-1 靶标：钙调磷酸酶样 EF 手蛋白 CHP1/chpf-1 和调节蛋白 CalciNeurin PPP3R1/cnb-1 的亚基，在 dve-1 突变体中被下调。我的初步研究表明，cnb-1 或 chpf-1 的突变会破坏重塑过程中的突触消除。我的拟议的工作将确定 CNB-1 的功能要求和行动地点，并确定钙调神经磷酸酶和蛋白酶体功能对突触消除的贡献（目标 1）。在目标 2 中，我将定义 chpf-1 如何有助于突触消除和维护。在目标 3 中，我将确定额外的通过使用神经元特异性 RNA-seq 确定 dve-1 在重塑途径中的潜在靶标。我提议的工作将增进我们对重塑和监管机制的理解，可能为未来的探索。