Regulation of epithelial function using targeted nanowires

使用靶向纳米线调节上皮功能

• 批准号: 10453894
• 负责人: Tejal A. Desai
• 金额: $ 63.13万
• 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/10453894
• 关键词: Actins; Adopted; Affect; Air; Antibodies; Apical; Architecture; Biological Assay; CD47 gene; Cell Adhesion Molecules; Cell model; Cell physiology; Cells; Characteristics; Chronic; Chronic Disease; Clinical; Collaborations; Complex; Crosslinker; Cultured Cells; Cytoskeleton; Data; Differentiation and Growth; Drug Controls; Drug Delivery Systems; Engineering; Epithelial; Epithelial Attachment; Epithelial Cells; F-Actin; Goals; Growth; Human; Impairment; In Vitro; Inflammation; Inflammatory; Integrin alpha Chains; Integrins; Knowledge; Label; Laboratories; Ligand Binding; Liquid substance; Lung; Lung diseases; Measurement; Measures; Mechanics; Membrane; Methods; Microscopy; Molecular; Molecular Conformation; Morphology; Nanostructures; Nanotopography; Nasal Epithelium; Nasal Polyps; Nasal cavity; Nose; Organoids; Otolaryngology; Patients; Permeability; Pharmacology; Phenotype; Physiological; Polyps; Proteins; Proteome; Quality of life; Regulation; Resistance; Resolution; Role; Scaffolding Protein; Series; Specificity; Structure; Structure of mucous membrane of nose; Surface; Talin; Testing; Tight Junctions; Tissue Banks; Topical application; Work; airway epithelium; base; cell growth; chronic rhinosinusitis; cohort; cytokine; density; design; design and construction; electric impedance; flexibility; fluorescence lifetime imaging; improved; live cell microscopy; macromolecule; nanoscale; nanowire; novel; novel therapeutics; particle; polycaprolactone; polyposis; pulmonary function; scaffold; sensor; subcutaneous; success; 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.

项目概要 鼻腔是临床上可接近的结构，适合局部应用纳米级 这种方法的成功需要利用颗粒来促进药物输送并控制局部炎症。 我们设计并构建了具有高水平特异性和活性的底物。 与抗β1整合素抗体缀合的可生物降解的聚己内酯（PCL）纳米线。 整合素纳米线将在培养细胞模型上进行测试，包括分化良好的原代人肺和 鼻气道上皮细胞，能够改变屏障功能、刺激转胞吞作用并影响细胞生长 初步数据支持我们开发抗整合素纳米线的能力。 增加或减少紧密连接的渗透性，取决于几种互补的成分。 方法将用于确定不同成分的抗整合素纳米线的作用机制， 主要关注它们对与紧密连接和整合素相关的细胞质支架蛋白的影响 调节肌动蛋白细胞骨架，这包括基于候选和发现的分子方法。 识别纳米线驱动的细胞质支架蛋白质组变化和超分辨率。 显微镜将用于测量抗整合素纳米线对天然体内连接和整合素的影响 一个目标是建立刺激顶端整合素的模式，作为一种药理学上易于处理的方法。 可以优先切换为改善呼吸道上皮屏障功能或 我们还将测试抗整合素纳米线对药物跨上皮屏障的影响。 源自鼻息肉的上皮，其紧密连接受损，部分去极化，并且缺乏 这些体外研究将评估纳米线作为治疗慢性病的潜在平台。 鼻窦炎伴鼻息肉病，这是一种严重损害生活质量的慢性疾病， 常与肺部疾病有关。