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.

晚期或终末期肺部疾病，如肺纤维化、肺气肿和囊性纤维化，是一种常见的疾病