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The molecular architecture of perineuronal nets

神经周围网络的分子结构

基本信息

批准号：
10455609
负责人：
Samuel Bouyain
金额：
$ 40.66万
依托单位：
UPSTATE MEDICAL 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：
2021-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10455609
关键词：
Architecture Binding Binding Proteins Biochemical Biological Assay CSPG3 gene Carbohydrates Cell Adhesion Molecules Cell Surface Proteins Cell Surface Receptors Cell surface Chondroitin Sulfate Proteoglycan Complex Crystallization Data Development Disease Event Exhibits Extracellular Matrix Extracellular Matrix Proteins Glycosaminoglycans Goals Health Hyaluronan In Vitro Label Lead Learning Life Ligands Link Macromolecular Complexes Memory Methodology Molecular Molecular Structure Neuraxis Neuronal Plasticity Neurons Neurophysiology - biologic function Pathogenesis Physiological Play Population Protein Tyrosine Phosphatase Proteins Reagent Recovery Role Specificity Stimulus Structure Surface Synapses Techniques Therapeutic Work X-Ray Crystallography aggrecan brevican cognitive function complex R contactin design developmental plasticity experimental study grasp in vivo information processing innovation insight interest janusin link protein macromolecular assembly nerve injury nervous system disorder neurodevelopment novel protein protein interaction receptor receptor binding relating to nervous system response synaptogenesis tool versican

项目摘要

Perineuronal nets (PNNs) are conspicuous neural extracellular matrix (ECM) structures that have garnered significant interest over the last decade for the critical roles they play in neural developmental plasticity. These complex macromolecular structures are implicated in an array of cognitive functions, and are altered in a variety of neurological disorders. Despite the growing interest in PNN functions, the mechanisms by which they modulate neural functions are poorly understood, because there are currently no tools or techniques to manipulate PNNs specifically. We surmise that our inability to target and disrupt PNNs is primarily driven by a lack of understanding of their molecular composition or structure. Our goal in this proposal is to conduct a structure-function analysis of known PNN components as well as to identify proteins that anchor nets to neuronal surfaces. Using a powerful combination of in vitro and in vivo approaches, we have obtained strong preliminary data detailing how the newly identified PNN component receptor protein tyrosine phosphatase zeta (RPTPζ) associates with tenascin-R (TNR) within PNNs at a molecular level. Furthermore, our data indicate that the RPTPζ•TNR complex anchors PNNs to the neuronal cell surface via the GPI-linked protein contactin-1 (CNTN1), which makes CNTN1 the first surface binding protein for PNNs ever identified. Our central hypothesis is that there are a set of unique components and receptors of PNNs that nucleate PNNs and anchor them to specific neuronal cell surfaces, thereby defining their unique structure and functions. The overall objective of this proposal is to identify PNN-specific components and dissect the formation of PNNs through a unique combination of proximity-labeling assays, protein-binding assays, and protein X-ray crystallography in order to create the tools to target and manipulate these structures specifically and precisely. Our long-term goal is then to use these tools to dissect PNN function in order to better understand disease pathogenesis and ultimately to target PNNs therapeutically. Guided by our strong preliminary data, this proposal seeks to discover the unique components that guide the assembly of PNNs by pursuing three non-overlapping specific aims: 1) defining the role of the RPTPζ•TNR complex in anchoring PNNs to neuronal surfaces; 2) pursuing the biochemical and structural characterization of interactions between ACAN, HAPLN1, and TNR; and 3) identifying cell surface receptors and novel components of PNNs. The proposed work is significant because it will attempt to identify the key unique components that contribute to the formation and thereby function of PNNs. Successful completion of the aims will provide key insights and reagents to manipulate PNNs specifically and precisely and ultimately understand their functional mechanisms. This approach is innovative because it brings together a novel combination of physiological, biochemical and structural approaches to investigate these important macromolecular assemblies in the central nervous system. Ultimately, the proposed work could be transformative for the field and lead to key mechanistic insights into of PNN function in health and disease.

神经周围网络（PNNs）是一种显著的神经细胞外基质（ECM）结构