Matrix and Bioreactors for Human Lung Regeneration

用于人肺再生的基质和生物反应器

• 批准号: 8601879
• 负责人: LAURA E NIKLASON
• 金额: $ 64.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601879
• 关键词: Address; Adhesions; Animals; Architecture; Automobile Driving; Behavior; Biomedical Engineering; Bioreactors; Blocking Antibodies; Blood Vessels; Cell physiology; Cells; Cessation of life; Chronic; Chronic lung disease; Confocal Microscopy; Cues; Cystic Fibrosis; Cytoskeleton; Data; Development; Disease; Elements; Environmental air flow; Epithelial; Evaluation; Event; Experimental Models; Extracellular Matrix; Feasibility Studies; Gases; Genes; Goals; Growth; Human; Image; Imaging Device; Immunohistochemistry; Infection; Instruction; Knock-out; Knowledge; Laboratories; Lung; Lung Transplantation; Lung diseases; Maintenance; Measures; Mechanical ventilation; Mechanics; Mediating; Mesenchymal; Methods; Mission; Modality; Morbidity - disease rate; Morphogenesis; Natural regeneration; Patients; Peptides; Perfusion; Phenotype; Physiological; Preparation; Principal Investigator; Process; Proliferating; Proteins; Proteomics; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonary alveolar structure; Research; Respiratory Failure; Respiratory physiology; Rodent; Slice; Staging; Structure; Structure of parenchyma of lung; Survival Rate; Symptoms; Technology; Testing; Therapeutic Intervention; Time; Tissues; Transmission Electron Microscopy; United States; Work; allograft rejection; cellular imaging; imaging modality; innovation; lung development; lung imaging; lung regeneration; lung repair; member; mortality; novel; repaired; research study; scaffold; success; tool

Advanced or end-stage lung diseases, such as pulmonary fibrosis, emphysema, and cystic fibrosis, are a major cause of morbidity and mortality in the United States. Although lung transplantation is a viable alternative for some patients, the 5-year survival rate of approximately 50% (primarily due to chronic allograft rejection and/or infection) limits this modality as a long-term therapy. Moreover, the scarcity of donated lungs and the short graft viability times post-expiant are major limitations. Thus, there is a desperate need both for understanding pathophysiologic mechanisms in chronic lung diseases as well as for devising innovative methods to repair or bioengineer functional lungs. Thus, this proposal will test the hypothesis that the lung extracellular matrix (ECM) drives the proper localization, differentiation, and function of lung cells and is the key contributor to normal lung repair and regeneration. With a long-term goal of regenerating a functional human lung, we propose to critically examine the constitutive makeup ofthe decellularized lung ECM and to develop new tools for assessing lung matrix structure and function. Further, we propose to develop a human lung bioreactor that allows for optimal preparation of decellularized human lung matrices while maintaining physiologic ventilation and perfusion. Among the questions to be addressed are: 1) what are the key components of lung ECM that drive cellular behavior and function? 2) How can we better assess the barrier function and structure of lung ECM? 3) Can we develop a bioreactor that will allow a human lung to be decellularized and subsequently recellularized while undergoing mechanical ventilation and vascular perfusion? Work in this UOl application will be instrumental forthe success ofthe Lung Regeneration Consortium, because we will generate a basic and comprehensive understanding ofthe lung matrix that is used as a substrate for lung growth. We will also develop tools and bioreactors that will enable other Consortium members to utilize and leverage our findings. RELEVANCE (See instructions): The relevance ofthis research is to begin studying the feasibility of regenerating a functional human lung in the laboratory. Studies proposed will comprehensively define the protein makeup ofthe normal human lung, will devise novel methods of imaging the cellular repopulation of human lung tissues, and will develop a novel bioreactor in which human lungs can be regenerated.

晚期或末期肺部疾病，例如肺纤维化，肺气肿和囊性纤维化，是一种 美国发病和死亡率的主要原因。尽管肺移植是可行的 某些患者的替代品，5年生存率约为50％（主要是由于慢性 同种异体移植排斥和/或感染）将这种方式限制为长期治疗。而且，稀缺 捐赠的肺部和短期后培养时间是主要局限性。因此，有一个 迫切需要了解慢性肺疾病中的病理生理机制 用于设计创新方法来修复或生物工程功能性肺。因此，该建议将测试 假设肺细胞外基质（ECM）推动了适当的定位，分化和 肺部细胞的功能，是正常肺修复和再生的关键因素。长期目标 为了再生功能性的人肺，我们建议批判性地检查构成的构成 脱细胞肺ECM并开发用于评估肺基质结构和功能的新工具。更远， 我们建议开发人类肺生物反应器，以最佳的脱细胞制备 肺部矩阵，同时保持生理通气和灌注。在要解决的问题中 是：1）驱动细胞行为和功能的肺ECM的关键成分是什么？ 2）我们怎么能 更好地评估肺ECM的屏障功能和结构？ 3）我们可以开发一个可以允许的生物反应器 经过机械通气的同时进行脱细胞并随后重新细胞化的人肺 和血管灌注？在此UOL应用中的工作将有助于肺的成功 再生财团，因为我们将对肺部产生基本而全面的理解 用作肺部生长的底物的基质。我们还将开发工具和生物反应器 使其他财团成员能够利用和利用我们的发现。 相关性（请参阅说明）： 这项研究的相关性是开始研究重生在 实验室。提出的研究将全面定义正常人肺的蛋白质构成， 将设计成像人类肺组织细胞重生的新方法，并将发展 可以再生的人类肺的新型生物反应器。