Synthetic mucins in epithelial models to probe virus-mucin interactions

上皮模型中的合成粘蛋白用于探测病毒-粘蛋白相互作用

• 批准号: 10655654
• 负责人: Jessica Kramer
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655654
• 关键词: Adhesions; Amino Acids; Antiviral Agents; Binding; Biology; Cell surface; Cells; Complex; Development; Diet; Diffusion; Disease; Drug Delivery Systems; Engineering; Epithelial Cells; Epithelium; Evolution; Future; Glycocalyx; Glycoproteins; Health; Heterogeneity; Host Defense; Human; Hydration status; Immunity; Infection; Jellyfish; Knowledge; Life; Life Cycle Stages; Lubrication; Malignant Neoplasms; Mentors; Modeling; Molecular; Molecular Weight; Mucins; Mucous body substance; Outcome; Pathway interactions; Pattern; Peptides; Play; Polymers; Polysaccharides; Prevention strategy; Proteins; Role; Sialic Acids; Specificity; Structure; Tissues; Underrepresented Populations; Vertebral column; Viral; Viral Genes; Virus; Virus Diseases; biophysical properties; chemical property; citizen science; disease transmission; equity, diversity, and inclusion; glycosylation; improved; novel therapeutics; nutrient absorption; pathogen; polymerization; polypeptide; preference; response; sugar; surface coating; tissue tropism

PROJECT SUMMARY Mucin glycoproteins are the essential component of mucus and the epithelial cellular glycocalyx. Mucins are essential for life in creatures from jellyfish to humans and play roles in hydration, lubrication, nutrient absorption, and host defense against pathogens. Mucin glycosylation is regulated by complex enzymatic pathways subject to flux, resulting in heterogeneous and variable glycan patterns that vary between tissues and species, and that evolve in response to diet and disease. The Kramer Lab is developing synthetic mucins, or synMUCs, that harness the chemical and biophysical properties of native mucins but have molecularly tunable structures. Polymerization of glycosylated amino acid N-carboxyanhydrides affords high molecular weight polypeptides with the native peptide and glycan linkages. Compared to short peptides, polysaccharides, or traditional polymers bearing attached sugars, synMUCs are the most authentic mucin mimics to date. The synMUCs will be applied in engineered models of the glycocalyx and secreted mucus. These models will find broad future application in studies of epithelial biology with application in cancer, drug delivery, immunity, and infection. Since mucins are on the front lines of cellular defense, diverse viruses have evolved strategies to adhere to their glycans, alter them, and even use them to enter host cells for replication. Virus-mucin binding can have outcomes on viral diffusion, tissue specificity, and replication but molecular details are lacking due to mucin heterogeneity. We will chemoenzymatically modify our synMUCs to display virus-binding sialic acid glycans. Viral binding preferences for various sialic acid structures in different densities and from varied peptide backbone compositions will be defined. The sialic-acid-bearing-synMUCs will be utilized to probe how mucins in the glycocalyx vs mucus regulate adhesion, cell entry and replication, tissue tropism and viral gene evolution. This knowledge will shed light on fundamental aspects of the viral life cycle and may assist in improving human health though development of new antiviral therapeutics and disease transmission prevention strategies. Additionally, scientific citizenship and mentoring are a priority and active involvement in supporting equity, diversity and inclusion of underrepresented groups in STEM will be a focus for the duration of the project and beyond.

项目总结