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）：美国的晚期或终阶段肺部疾病，例如肺纤维化，肺气肿和囊性纤维化，是美国发病率和死亡率的主要原因。尽管肺移植是某些患者的可行替代方法，但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。此外，捐赠的肺部稀缺性和移植后的短期生存时间是主要局限性。因此，我迫切需要了解慢性肺部疾病中的病理生理机制，以及为修复或生物工具功能性肺部设计创新方法。因此，该提案将检验以下假设：肺外基质（ECM）驱动肺细胞的适当定位，分化和功能，并且是导致Norml肺部修复和再生的关键。我们的长期目标是再生功能性的人肺，我们建议批判性地检查脱细胞肺ECM的构构，并开发用于评估肺部基质结构和功能的新工具。此外，我们建议开发人类肺生物反应器，该生物反应器可在维持生理通气和灌注的同时最佳制备脱细胞的人肺基质。要解决的问题包括：1）驱动细胞行为和功能的肺ECM的关键组成部分是什么？ 2）我们如何更好地评估肺ECM的屏障功能和结构？ 3）我们可以开发一种生物反应器，该生物反应器将使人的肺在接受机械通气和血管灌注的同时进行脱细胞并随后重新细胞化吗？该U01应用程序中的工作将有助于肺部再生财团的成功，因为我们将对肺部基质产生基本而全面的理解，该理解被用作肺部生长的基础。我们还将开发工具和生物反应器，以使其他财团成员能够利用和利用我们的发现。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。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的细胞重生的新方法，并将开发一种新型的生物反应器，可以在其中再生人类肺。