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Cell membrane-targeting proteoglycan chimeras as selective growth factor signaling actuators

作为选择性生长因子信号传导执行器的细胞膜靶向蛋白聚糖嵌合体

基本信息

批准号：
10588085
负责人：
Kamil Godula
金额：
$ 49.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2023-06-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588085
关键词：
Anabolism Automobile Driving Basic Science Binding Biochemical Biological Biological Assay Biological Products Biomedical Research Carrier Proteins Cell Differentiation process Cell Line Cell Proliferation Cell Therapy Cell membrane Cell physiology Cell surface Cells Chemicals Chimera organism Communities Complex Data Development Disease Disease Management Elements Engineering Enzymes Equilibrium FGF1 gene FGF2 gene Family Fibroblast Growth Factor Fibroblast Growth Factor Receptor 1 Fibroblast Growth Factor Receptor 2 Fibroblast Growth Factor Receptors Future Gene Expression Genetic Engineering Goals Growth Factor Growth Factor Inhibition Growth Factor Interaction Growth Factor Receptors Harvest Heparan Sulfate Biosynthesis Heparan Sulfate Proteoglycan Heparitin Sulfate Heterogeneity Immune System Diseases Laboratories Ligands Link Lipids Lysosomes Macrophage Malignant Neoplasms Mediating Membrane Metabolic Methods Mus Mutation Oligosaccharides Outcome Patients Polysaccharides Production Proliferating Property Protein Family Proteoglycan Proxy Reagent Recombinants Recycling Regenerative Medicine Regulation Regulatory Element Scaffolding Protein Signal Pathway Signal Transduction Signaling Protein Specificity Structure Structure-Activity Relationship Sulfate System Techniques Technology Therapeutic Therapeutic Uses Tissue Engineering Work analytical tool biological research cancer therapy cellular engineering embryonic stem cell extracellular improved inorganic phosphate man member mimetics mutant nerve stem cell new technology polysulfated glycosaminoglycan prototype receptor regeneration potential response scaffold tool

项目摘要

Project Summary Growth factor (GF)-based therapies hold great promise for tissue engineering, cancer treatment, and regenera- tive medicine but controlling their activity and selectivity can be challenging. GFs act as ligands for membrane- receptors controlling signaling cascades that drive gene expression and cellular functions, such as proliferation and differentiation. Tools that can selectively activate or suppress GF-mediated signaling activity in cells are needed to achieve control over the activity of these molecules and improve their therapeutic properties. Heparan sulfate (HS) proteoglycans (PGs), while often overlooked, are uniquely suited for this purpose, as they often serve as coreceptors for GFs at the cell surface. By promoting the formation of complexes between GFs and their receptors, they balance competing signaling pathways and regulate cellular responses. While the structure and activity of HS on cells can be controlled, to some extent, through genetic engineering of their biosynthesis, chemical tools for remodeling cell-sulfate HS to attain GF-binding specificity would be much mor general and better suited for therapeutic applications. This project establishes such tools, termed neoPG chimeras, that will be able to selectively activate or inhibit GF signaling activity in cells. This will be achieved by taking advantage of the GF-binding selectivities of recombinant HS polysaccharides produced through systematic mutation of HS biosynthetic enzymes in laboratory cell lines. The recombinant HS polysaccharides will be harvested, character- ized for GF binding specificity and merged with functional elements for targeting to the cells. Membrane targeting neoPG chimeras will be developed to promote GF association with receptors at the cell surface and promote GF signaling activity (Aim 1). Lysosome-targeting neoPG chimeras will be used to drive extracellular GFs into the cells for degradation, thus inhibiting signaling activity (Aim 2). The focus of this study will be on establishing and validating neoPG chimeras as actuators of signaling by members of the Fibroblast Growth Factor family of pro- teins in the context of cellular proliferation and differentiation. However, many other classes of GFs require cell surface HS for function and the new tools are expected to find broad application in many different aspects of biomedical research and GF-based therapies.

项目总结