Engineering ex vivo models of lung cancer and chemoprevention

肺癌和化学预防的离体工程模型

• 批准号: 10038486
• 负责人: Chelsea M Magin
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038486
• 关键词: Accounting; Address; Adenocarcinoma; Animal Cancer Model; Animal Model; Animals; Award; Biocompatible Materials; Biology; Biomedical Engineering; Cancer Biology; Cancer Etiology; Carcinogen exposure; Carcinogens; Cells; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical Chemoprevention; Clinical Trials; Collagen; Complex; Consumption; Data; Development; Diagnosis; Disease; Engineering; Foundations; Funding; Gene Expression; Generations; Goals; Histology; Histopathologic Grade; Human; Hydrogels; Individual; Intercept; Intervention; Lesion; Lesion by Stage; Life; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Methods; Modeling; Modulus; Molecular; Mus; Pathogenesis; Patients; Pharmaceutical Preparations; Positioning Attribute; Prevention; Reporting; Research Personnel; Risk; Scientist; Screening procedure; Slice; Smoker; Squamous cell carcinoma; Statistical Models; Stimulus; Structure of parenchyma of lung; System; Technology; Testing; Thinness; Time; Tissues; Tobacco-Associated Carcinogen; United States; Urethane; Work; base; cancer chemoprevention; cancer diagnosis; cancer therapy; cell type; cost; cytokine; design; drug abuse prevention; drug testing; ethylene glycol; experimental study; high risk population; high throughput screening; human tissue; improved; in vivo; innovation; intervention effect; lung cancer prevention; mortality; mouse model; novel; novel strategies; pre-clinical; premalignant; prevent; protein aminoacid sequence; response; screening; tool; tumor progression

PROJECT SUMMARY Lung cancer is a particularly devastating diagnosis accounting for 24% of all cancer deaths in the United States. A new lung cancer diagnosis occurs every 2.3 minutes in the U.S. and more than half of these diagnoses are in former smokers. This identifiable high-risk population is an ideal target for chemoprevention. Intercepting the emergence of lung tumors is key to reducing the burden of lung cancer mortality, however, studies on prevention drugs rely on animal models and are costly, time consuming, and require large numbers of animals. Precision-cut lung slices (PCLS) address these challenges by retaining the complexity of living tissue while enabling disease studies outside the animal. These thin slices of mouse lung tissue grown in a dish can be used for studying exposures that cause cancer and testing drugs that prevent cancer. PCLS have not yet been used for studies of early lung cancer due to breakdown of the tissue slices outside the animal. We have developed a new approach that uses bioengineered materials to support extended life of lung tissue grown outside a mouse. We propose to use this model to study early lung cancer and prevention drugs. We will optimize the conditions of our bioengineered PCLS to further increase the stability of lung tissue grown outside a mouse. We will expose PCLS to tobacco carcinogens to induce abnormalities in lung cells that are known to precede lung tumors in mice. When we can induce early lung cancer in the PCLS, we will test the effects of drugs known to prevent lung tumor development in mice to see if they also prevent or reverse development of early lung cancer in PCLS. We will also test four emerging prevention drugs to validate the use of our system for screening the efficacy of new compounds. Our bioengineered system could have a significant impact on how we generate the data supporting clinical trials of lung cancer prevention drugs. By making many individual slices from a single mouse lung, it will reduce the number of animals and cost of the studies required to test multiple conditions and drugs. This approach will also significantly shorten the time needed to study how prevention drugs work and their impact on lung biology by studying live tissue in a dish rather than in an animal. Developing this system for mouse tissue will build the foundation for using human tissue. This will directly impact patients at risk of lung cancer and improve how they are screened for clinical trials or individual treatments. With this exploratory award, we anticipate delivering a new model of early lung cancer that will support further funding for advanced studies, leading to an increase in the use of prevention drugs in high risk populations and a reduction in lung cancer mortality.

项目摘要 肺癌是一种特别具有破坏性的诊断，占美国所有癌症死亡的24%。 States.在美国，每2.3分钟就有一个新的肺癌诊断，其中超过一半的人 诊断是在前吸烟者。这种可识别的高危人群是化学预防的理想目标。 阻断肺部肿瘤的出现是降低肺癌死亡率负担的关键，然而， 预防药物的研究依赖于动物模型，成本高，耗时长，需要大量的数据 动物。精确切割肺切片（PCLS）通过保留生活的复杂性来应对这些挑战 组织，同时能够在动物体外进行疾病研究。这些小鼠肺组织的薄片生长在 这种培养皿可用于研究致癌物质的暴露和测试预防癌症的药物。PCLS具有 由于组织切片在动物体外分解，因此尚未用于早期肺癌的研究。我们 已经开发出一种新的方法，使用生物工程材料来支持延长肺组织的寿命 在老鼠体外生长我们建议使用该模型来研究早期肺癌和预防药物。我们 将优化我们的生物工程PCLS的条件，以进一步增加肺组织生长的稳定性， 一只老鼠外。我们将PCLS暴露于烟草致癌物中，以诱导肺细胞的异常， 已知在小鼠肺肿瘤之前。当我们可以在PCLS中诱导早期肺癌时，我们将测试 已知可以预防小鼠肺肿瘤发展的药物的作用，看看它们是否也可以预防或逆转 PCLS中早期肺癌的发展。我们还将测试四种新兴的预防药物，以验证 使用我们的系统筛选新化合物的功效。我们的生物工程系统可以 这对我们如何生成支持肺癌预防药物临床试验的数据产生了重大影响。通过 从一只老鼠的肺上制作许多单独的切片，这将减少动物的数量和成本。 需要测试多种条件和药物的研究。这种做法也将大大缩短时间 需要通过研究培养皿中的活组织来研究预防药物的工作原理及其对肺部生物学的影响 而不是在动物身上。本系统的建立为进一步应用于人体组织器官移植奠定了基础 组织.这将直接影响有肺癌风险的患者，并改善他们的临床筛查方式。 试验或个别治疗。有了这个探索性的奖项，我们预计将提供一个新的早期肺模型， 癌症，这将支持进一步资助先进的研究，从而增加使用预防 在高危人群中使用药物和降低肺癌死亡率。

项目成果

3D-bioprinted, phototunable hydrogel models for studying adventitial fibroblast activation in pulmonary arterial hypertension.

• DOI: 10.1088/1758-5090/aca8cf
• 发表时间: 2022-12-19
• 期刊: BIOFABRICATION
• 影响因子: 9
• 作者: Davis-Hall, Duncan;Thomas, Emily;Pena, Brisa;Magin, Chelsea M.
• 通讯作者: Magin, Chelsea M.

3D Bioprinting Phototunable Hydrogels to Study Fibroblast Activation.

3D 生物打印光可调水凝胶用于研究成纤维细胞激活。

• DOI: 10.3791/65639
• 发表时间: 2023
• 期刊: Journal of visualized experiments : JoVE
• 作者: Tanneberger,AliciaE;Blair,Layla;Davis-Hall,Duncan;Magin,ChelseaM
• 通讯作者: Magin,ChelseaM

Alveolar epithelial cells and microenvironmental stiffness synergistically drive fibroblast activation in three-dimensional hydrogel lung models.

• DOI: 10.1039/d2bm00827k
• 发表时间: 2022-12-06
• 期刊: BIOMATERIALS SCIENCE
• 影响因子: 6.6
• 作者: Caracena, Thomas;Blomberg, Rachel;Hewawasam, Rukshika S.;Fry, Zoe E.;Riches, David W. H.;Magin, Chelsea M.
• 通讯作者: Magin, Chelsea M.