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Evolving New Glycosaminoglycan Mimetics

不断发展的新糖胺聚糖模拟物

基本信息

批准号：
9789672
负责人：
Linda C Hsieh-Wilson
金额：
$ 37.64万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789672
关键词：
3-Dimensional Affinity Alzheimer&apos s Disease Anti-inflammatory Anticoagulants Antithrombin III Architecture Autoimmune Diseases Avidity Binding Binding Proteins Binding Sites Biological Process Biological Response Modifiers Blood coagulation CXCL10 gene CXCL11 gene CXCL9 gene CXCR3 gene Cell Proliferation Cell division Cells Chemicals Chemotaxis Chondroitin Sulfates Collaborations Communicable Diseases Consumption Dementia Development Directed Molecular Evolution Disaccharides Disease Drug Targeting Epitopes Event FGF2 gene Glycopeptides Glycosaminoglycans Goals Growth Factor HIV Heparin Heparitin Sulfate Immune response In Vitro Individual Inflammation Inflammation Mediators Inflammatory Laboratories Lead Libraries Macular degeneration Malignant Neoplasms Mediating Messenger RNA Methods Microtubule-Associated Proteins Neoplasm Metastasis Nerve Degeneration Neurodegenerative Disorders Neurons Oligosaccharides Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathologic Processes Pathology Peptides Pharmaceutical Preparations Physiological Physiological Processes Play Polymers Polysaccharides Proteins RANTES Research Role Sampling Signal Pathway Signal Transduction Signaling Protein Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Studies Time Translations Unspecified or Sulfate Ion Sulfates Variant Work Wound Healing angiogenesis base cell motility chemokine human disease immunoregulation in vivo insight interest link protein migration mimetics monomer nanomolar neurodevelopment neuronal growth neutralizing antibody novel novel strategies novel therapeutic intervention novel therapeutics pathogen polymerization preference protein aminoacid sequence protein complex receptor scaffold stem sulfation tau Proteins tau interaction tool transmission process uptake

项目摘要

Project Summary Glycosaminoglycans (GAGs) play important roles in many physiological and pathological events such as cell division, inflammation, neural development, and cancer metastasis. The long polysaccharide chains of GAGs contain various sulfated disaccharides that are organized into sulfate-rich and under-sulfated domains. This rich structural diversity enables GAGs such as heparan sulfate (HS) to interact with numerous proteins and regulate key signaling pathways. However, efforts to understand their structure-function relationships and harness their therapeutic potential have been hampered by the chemical complexity of GAGs and a lack of tools. At present, there are no tools to manipulate the interactions of GAGs with specific proteins of interest, thus complicating efforts to pinpoint their precise roles. The goal of this project is to develop novel chemical probes for selectively modulating GAG activity. We will use a directed evolution-based approach to create a new class of GAG mimetics – multivalent glycopeptides appended with short, active HS motifs – to modulate specific HS-protein interactions. Random sampling of peptide sequences by directed evolution should allow for the selection of structures containing the ideal number and arrangement of HS motifs. In addition to optimal HS clustering, selected peptides should contain peptide motifs recognized by the protein of interest, thus generating highly specific GAG probes. In Aim 1, we will work in collaboration with the Krauss laboratory to develop the approach and generate HS mimetics that interact selectively with fibroblast growth factor 2 (FGF2), a key growth factor involved in cell migration, angiogenesis, and differentiation. In Aim 2, we will evolve glycopeptides that bind to specific forms of tau, a microtubule-associated protein linked to dementias such as Alzheimer's disease and Parkinson's disease. We will use these HS mimetics to understand the mechanisms underlying tau uptake into neurons and neurodegeneration. In addition, we will explore whether our mimetics can block the intercellular spreading of tau and its pathogenic consequences. In Aim 3, we will evolve glycopeptides that bind chemokines (specifically CXCL9, CXCL10 and CXCL11), a class of therapeutically important proteins that are key mediators of inflammation. Our probes should provide unique insights into the paradoxical functional redundancy of chemokines, enabling us to tease apart their individual roles. Together, these studies will produce a novel class of GAG-based probes for understanding the physiological functions of GAGs and may ultimately lead to new therapeutic leads or approaches to diseases such as cancer, neurodegenerative diseases, inflammatory and autoimmune disorders, and infectious diseases.

项目总结