Regulation of epithelial function using targeted nanowires

使用靶向纳米线调节上皮功能

• 批准号: 10677028
• 负责人: Tejal A. Desai
• 金额: $ 61.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677028
• 关键词: Actins; Adopted; Affect; Air; Antibodies; Apical; Architecture; Biological Assay; CD47 gene; Cell Adhesion Molecules; Cell Differentiation process; Cell model; Cell physiology; Cells; Characteristics; Chronic; Chronic Disease; Clinical; Collaborations; Complex; Crosslinker; Cultured Cells; Cytoplasm; Cytoskeleton; Data; Drug Controls; Drug Delivery Systems; Engineering; Epithelial Cells; Epithelium; F-Actin; Goals; Growth; Human; Impairment; In Vitro; Inflammation; Inflammatory; Integrins; Knowledge; Label; Laboratories; Ligand Binding; Liquid substance; Lung; Lung diseases; Measurement; Measures; Mechanics; Membrane; Methods; Molecular; Molecular Conformation; Morphology; Nanostructures; Nanotopography; Nasal Epithelium; Nasal Polyps; Nasal cavity; Nose; Organoids; Otolaryngology; Patients; Permeability; Phenotype; Physiological; Polyps; Proteins; Proteome; Quality of life; Regulation; Resistance; Role; Scaffolding Protein; Series; Specificity; Structure; Structure of mucous membrane of nose; Surface; Talin; Testing; Tight Junctions; Tissue Banks; Topical application; Work; airway epithelium; cell growth; chronic rhinosinusitis; cohort; cytokine; density; design; design and construction; electric impedance; flexibility; fluorescence lifetime imaging; improved; live cell microscopy; macromolecule; manufacture; nanoscale; nanowire; novel; novel therapeutics; particle; pharmacologic; polycaprolactone; polyposis; pulmonary function; scaffold; sensor; subcutaneous; success; superresolution microscopy; transcytosis

PROJECT SUMMARY The nasal cavity is a clinically accessible structure that is amenable to the topical application of nanoscale particles to facilitate drug delivery and control local inflammation. The success of this approach requires substrates with a high level of specificity and activity. We have designed and constructed derivatizable, biodegradable polycaprolactone (PCL) nanowires that are conjugated to anti-β1 integrin antibodies. Anti- integrin nanowires will be tested on cultured cell models, including well differentiated primary human lung and nasal airway epithelial cells, for the ability to alter barrier function, stimulate transcytosis, and affect cell growth and differentiation. Preliminary data supports our ability to develop anti-integrin nanowires with the capacity to either increase or decrease tight junction permeability, depending on composition. Several complementary approaches will be used to identify the mechanism of action for anti-integrin nanowires of different composition, focusing primarily on their effects on cytoplasmic scaffold proteins associated with tight junctions and integrins that regulate the actin cytoskeleton. This includes candidate and discovery based molecular methods to identify nanowire-driven changes to the cytoplasmic scaffold proteome. Live cell and super resolution microscopy will be used to measure the effects of anti-integrin nanowires on junctions and integrins in a native context. One goal is to establish modes of stimulating apical integrins as a pharmacologically tractable approach that can be preferentially switched to either improve respiratory epithelial barrier function or to facilitate drug delivery across epithelial barriers. We also will test the effects of anti-integrin nanowires on epithelia derived from nasal polyps, which have impaired tight junctions, are partially de-polarized, and lack growth control. These in vitro studies will evaluate nanowires as a potential platform to treat chronic rhinosinusitis with nasal polyposis, a chronic condition that significantly impairs quality of life and that is frequently associated with lung disease.

项目总结