Bioengineered Multi-Cell Type Organoids For Airways Disease Modeling

用于气道疾病建模的生物工程多细胞类器官

基本信息

批准号：
10201733
负责人：
Sean Vincent Murphy
金额：
$ 43.64万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201733
关键词：
3-Dimensional Address Air Airway Disease Animal Model Animals Antibiotic Resistance Architecture Award Bacterial Attachment Site Bacterial Infections Bacterial Model Biochemical Biological Biomechanics Biomedical Engineering Biomimetics Cause of Death Cell Culture System Cell Culture Techniques Cell Survival Cells Cessation of life Cilia Clinical Data Collection Complex Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Developing Countries Development Disease Disease model Drug Kinetics Endothelium Epithelial Epithelial Cells Experimental Models Extracellular Matrix Extracellular Matrix Proteins Extracellular Protein Frequencies Functional disorder Genetic Growth Growth Factor Heterogeneity Human Hydrogels In Vitro Incidence Infection Investigation Knowledge Life Liquid substance Lung Lung diseases Medical Membrane Mesenchyme Microbial Biofilms Modeling Morphology Mucociliary Clearance Mucous body substance Organoids Outcome Pathogenesis Pathology Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phenotype Physiological Preclinical Testing Prevalence Production Property Pseudomonas aeruginosa Research Proposals Respiration Respiratory Tract Infections Respiratory physiology Signal Transduction Smoking Structure of parenchyma of lung Structure of respiratory epithelium Study models Surface Testing Therapy Evaluation Tissue Engineering Tissues Treatment outcome United States National Institutes of Health Work airway epithelium biophysical analysis cell type clinically relevant cost cystic fibrosis airway cystic fibrosis airway epithelia design drug discovery genetic risk factor improved in vitro Model in vivo monolayer multidisciplinary novel novel therapeutics preservation pressure soft tissue therapy development

项目摘要

PROJECT SUMMARY Respiratory diseases are among the leading causes of death worldwide. Respiratory disease caused by smoking, infections, and genetic factors together account for approximately 9.5 million deaths per year. Respiratory infection is the 3rd most common cause of death worldwide, and the leading cause of death in developing countries. Genetic risk factors are significant contributors to lung disease prevalence. For example, cystic fibrosis (CF) is ranked as one of the most widespread life-shortening genetic diseases2-4 with more than 70,000 people currently living with CF. Due to the high incidence; respiratory diseases are also among the most studied medical conditions. The study of respiratory diseases is significantly limited by a lack of suitable in vivo and in vitro models to investigate interactions between the respiratory epithelium, infection, and disease. Unfortunately animal models of lung disease differ significantly from humans in airway development and disease pathology, so often result in inaccurate and significantly flawed models, While some progress has been made in using human cell culture systems for disease modeling and drug discovery, current in vitro models are unable to reproduce the complex spatial morphology and allow biologically relevant cell-cell and cell-matrix interactions. The overall premise for the proposed work is that (a) in vivo animal models often differ significantly from humans in disease pathology and have significant cost limitations; and (b) current in vitro models of respiratory disease and bacterial pathogenesis do not recapitulate the complex tissue components and 3D architecture of the human airway epithelium. This collaborative R01 proposal is motivated by the critical need to address the current gaps and knowledge and overcome the limitations of current in vitro 2D cell culture models for airway disease modeling, therapy development, and pre-clinical testing. Our overall hypothesis is that recapitulation of the in vivo airway microenvironment will provide a more effective in vitro surrogate for airway disease modeling and therapy evaluation. To test this hypothesis, we will first generate bioengineered multicellular 3D airway organoids, supported by a lung extracellular matrix (ECM)-derived biogel with tunable biomechanical properties, to promote multicellular organization and function of healthy airway epithelium (Aim 1). Next we will evaluate whether 3D airway organoids containing CF airway epithelium can model disease pathology (Aim 2). Finally we will use this novel airway disease model to study the pathogenesis of P. aeruginosa (Aim 3). If awarded, this collaborative R01 will allow our multi-disciplinary and multi-institutional team to develop and evaluate 3D airway organoids as a more effective in vitro surrogate for airway disease modeling and therapy evaluation. Likely developments building on this work could include use of patient-specific airway organoid models for testing of personalized disease treatments, combined with collection of clinical data to validate the use of organoids to predict treatment outcomes and guide treatment.

项目摘要呼吸道疾病是全球死亡的主要原因之一。由吸烟，感染和遗传因素每年约为950万人死亡。呼吸道感染是全球第三大死亡原因，也是死亡的主要原因发展中国家。遗传危险因素是导致肺部疾病患病率的重要因素。例如，囊性纤维化（CF）被评为最广泛的遗传疾病之一，遗传疾病2-4超过目前有70,000人CF。由于发病率很高；呼吸道疾病也是大多数研究的医疗状况。缺乏合适的体内和体外模型，以研究呼吸上皮，感染和疾病。不幸的是，肺部疾病的动物模型与人类在气道发展中有显着差异和疾病病理学，因此经常导致模型不准确和明显有缺陷，而某些进展已有在使用人类细胞培养系统进行疾病建模和药物发现中制作，当前体外模型无法再现复杂的空间形态，并允许生物学相关的细胞细胞和细胞 - 矩阵相互作用。拟议工作的总体前提是（a）体内动物模型通常不同人类在疾病病理学中的显着范围很大，并且具有重大的成本限制；（b）体外电流呼吸道疾病和细菌发病机理的模型不会概括复杂的组织成分和人类气道上皮的3D建筑。该协作R01提案是由解决当前差距和知识并克服当前体外2D细胞的局限性的迫切需求气道疾病建模，治疗发展和临床前测试的培养模型。我们的整体假设是体内气道微环境的概括将提供更有效的体外替代气道疾病建模和治疗评估。为了检验这一假设，我们将首先生成生物工程的多细胞3D气道器官，由肺外基质（ECM）衍生的沼气支撑具有可调的生物力学特性，以促进健康气道的多细胞组织和功能上皮（AIM 1）。接下来，我们将评估3D Airway类器官是否含有CF气道上皮模型疾病病理学（AIM 2）。最后，我们将使用这种新型的气道疾病模型来研究铜绿假单胞菌的发病机理（AIM 3）。如果授予，此协作R01将允许我们的多学科和多机构的团队开发和评估3D Airway Ordanss作为更有效的体外替代物气道疾病建模和治疗评估。这项工作的发展可能包括使用特定于患者特异性飞行道的器官模型，用于测试个性化疾病治疗收集临床数据，以验证使用器官来预测治疗结果和指导治疗。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of a novel air-liquid interface airway tissue equivalent model for in vitro respiratory modeling studies.

DOI：
10.1038/s41598-023-36863-1
发表时间：
2023-06-22
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Leach, Timothy;Gandhi, Uma;Reeves, Kimberly D.;Stumpf, Kristina;Okuda, Kenichi;Marini, Frank C.;Walker, Stephen J.;Boucher, Richard;Chan, Jeannie;Cox, Laura A.;Atala, Anthony;Murphy, Sean V.
通讯作者：
Murphy, Sean V.