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

• 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
• 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

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.

项目摘要 生长因子（GF）的疗法对组织工程，癌症治疗和再生疗法具有很大的希望 医学但控制他们的活动和选择性可能具有挑战性。 GFS充当膜的配体 控制驱动基因表达和细胞功能的信号级联的受体，例如增殖 和分化。可以选择性激活或抑制细胞中GF介导的信号活性的工具是 需要控制这些分子的活性并改善其治疗特性。乙酰肝素 硫酸盐（HS）蛋白聚糖（PGS）虽然经常被忽略，但非常适合此目的 用作细胞表面GFS的共感受器。通过促进GFS和 他们的受体，平衡竞争信号通路并调节细胞反应。而结构 通过其生物合成的基因工程在某种程度上可以控制HS对细胞上HS的活性， 重塑细胞硫酸盐HS以达到GF结合特异性的化学工具将是一般的，并且 更适合治疗应用。该项目建立了这种工具，称为NEOPG Chimeras，将 能够选择性激活或抑制细胞中的GF信号传导活性。这将通过利用 通过系统突变HS产生的重组HS多糖的GF结合选择性 实验室细胞系中的生物合成酶。重组HS多糖将被收获，特征 - 用于GF结合特异性，并与功能元素合并以靶向细胞。膜靶向 NEOPG Chimeras将开发以促进与细胞表面受体的GF关联并促进GF 信号活动（AIM 1）。将溶酶体靶向NEOPG Chimeras将用于将细胞外GF驱动到 降解的细胞，从而抑制信号传导活性（AIM 2）。这项研究的重点将是建立和 验证NEOPG Chimeras作为促纤维细胞生长因子家族成员的信号传导的执行器 在细胞增殖和分化的背景下。但是，许多其他类别的GF需要单元格 表面HS用于功能，新工具应在许多不同方面找到广泛的应用 生物医学研究和基于GF的疗法。