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: 8224021
• 负责人: LAURA E NIKLASON
• 金额: $ 69.7万
• 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/8224021
• 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; 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 repair; member; mortality; novel; repaired; research study; scaffold; success; tool

DESCRIPTION (provided by applicant): 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-explant are major limitations. Thus, there i 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 norml lung repair and regeneration. With a long-term goal of regenerating a functional human lung, we propose to critically examine the constitutive makeup of the 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 U01 application will be instrumental for the success of the Lung Regeneration Consortium, because we will generate a basic and comprehensive understanding of the 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: The relevance of this research is to begin studying the feasibility of regenerating a functional human lung in the laboratory. Studies proposed will comprehensively define the protein makeup of the 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.

描述（由申请人提供）：晚期或终末期肺部疾病，如肺纤维化、肺气肿和囊性纤维化，是美国发病率和死亡率的主要原因。尽管肺移植对于某些患者是可行的替代方案，但约50%的5年存活率（主要由于慢性同种异体移植物排斥和/或感染）限制了这种方式作为长期治疗。此外，供体肺的稀缺性和移植后的短移植物存活时间是主要的限制。因此，迫切需要了解慢性肺部疾病的病理生理机制以及设计创新方法来修复或生物工程功能性肺。因此，该提议将测试肺细胞外基质（ECM）驱动肺细胞的适当定位、分化和功能并且是正常肺修复和再生的关键贡献者的假设。随着一个长期的目标是再生一个功能性的人肺，我们建议严格审查的脱细胞肺ECM的组成，并开发新的工具，用于评估肺基质的结构和功能。此外，我们建议开发一种人肺生物反应器，该生物反应器允许最佳制备脱细胞人肺基质，同时保持生理通气和灌注。要解决的问题包括：1）驱动细胞行为和功能的肺ECM的关键成分是什么？2)我们如何才能更好地评估肺ECM的屏障功能和结构？3)我们能否开发出一种生物反应器，使人的肺在进行机械通气和血管灌注的同时进行脱细胞和再细胞化？U 01应用程序中的工作将有助于肺再生联盟的成功，因为我们将对用作肺生长基质的肺基质有一个基本而全面的了解。我们还将开发工具和生物反应器，使其他联盟成员能够利用和利用我们的研究结果。相关性：这项研究的相关性是开始研究在实验室中再生功能性人肺的可行性。这项研究将全面定义正常人肺的蛋白质组成，将设计出成像人肺组织细胞再增殖的新方法，并将开发一种新的生物反应器，使人肺可以再生。