Dendritic spine morphology and the Ubiquitin pathway

树突棘形态和泛素通路

基本信息

批准号：
7388865
负责人：
Xiaolu Ang Cambronne
金额：
$ 2.53万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7388865
关键词：
Actins Acute Affect Binding Biological Assay Cells Classification Complex Computer software Cytoskeleton DNA Sequence Rearrangement Data Dendritic Spines Disease Dominant-Negative Mutation Down Syndrome Down-Regulation Epilepsy Excitatory Synapse F-Actin F-Box Proteins Fragile X Syndrome Green Fluorescent Proteins Head Hippocampus (Brain)Image In Vitro Individual Investigation Ligase Mediating Molecular Morphology N-Methyl-D-Aspartate Receptors Neurons Numbers Pathway interactions Phosphorylation Picrotoxin Proteasome Inhibitor Protein Overexpression Protein-Serine-Threonine Kinases RNA Interference Reaction Recruitment Activity Regulation Role SKP Cullin F-Box Protein Ligases Signal Transduction Specificity Structure Synapses Synaptic plasticity TP53 gene Ubiquitin Ubiquitination Vertebral column base density genetic regulatory protein human PLK1 protein in vivo knock-down nervous system disorder p27 Cell Cycle Protein p27 Enzyme Inhibitor postsynaptic presynaptic density protein 95 reconstitution research study serum-inducible kinase size two-photon ubiquitin-protein ligase

项目摘要

Dendritic spines in excitatory synapses can undergo dynamic actin-based morphological changes associated with synaptic plasticity. Recent examination into the molecular basis of this plasticity uncovered a role for SPAR, a RapGAP that targets to the PSD of dendritic spines. In turn, SPAR stability is regulated by serine/threonine kinase SNK. SNK phosphorylates SPAR, which promotes SPAR degradation through a proteasomal pathway. Nevertheless, the identity of the E3 Ub-ligases that target SPAR and how they are regulated is still unknown. Our investigation into the E3 Ub-ligases that target SPAR to regulate synaptic plasticity includes the following three major efforts: Aim 1 investigates roles for SCF Ub-ligases in SPAR degradation and the activation signals they recognize in the substrate; Aim 2 details a comprehensive approach to identify all E3 Ub-ligases that target SPAR; and Aim 3 examines how depletion of identified candidate E3 Ub-ligases affects dendritic spine morphology in primary hippocampal neurons. In addition to providing concrete evidence for the involvement of the Ub-pathway in the regulation of dendritic spine morphology, identification of the E3 Ub-ligases that mediate SPAR degradation is intrinsic to understanding the mechanism that may underlie a number of disorders associated with abnormal spine morphology and density, including general mental retardation, fragile-X syndrome, Down's syndrome, and epilepsy.

兴奋性突触中的树突状刺可经历基于动态肌动蛋白的形态变化具有突触可塑性。最近对这种可塑性的分子基础的检查发现了 SPAR，一种靶向树突状刺Psd的RapGAP。反过来，SPAR稳定性受丝氨酸/苏氨酸激酶SNK。 SNK磷酸化SPAR，从而促进SPAR通过蛋白酶体途径。然而，靶向晶石的E3 UB - 连接酶的身份及其如何受监管仍然未知。我们对靶向SPAR调节突触的E3 UB - 连接酶的调查可塑性包括以下三项主要工作：AIM 1调查SPAR中SCF UB - 连接酶的角色降解及其在底物中识别的激活信号；目标2详细详细介绍识别所有靶向SPAR的E3 UB - 连接酶的方法； AIM 3检查了鉴定的耗竭候选E3 UB - 连接酶影响原发性海马神经元的树突状脊柱形态。此外提供具体的证据，以参与UB-Pathway在树突状脊柱调节中形态学，介导SPAR降解的E3 UB - 杆酶的识别是理解的固有的可能是与异常脊柱形态相关的许多疾病的基础的机制密度，包括一般的智力低下，脆弱-X综合征，唐氏综合症和癫痫。