Matrix and Bioreactors for Human Lung Regeneration

晚期或终末期肺部疾病，如肺纤维化、肺气肿和囊性纤维化，是一种严重的慢性疾病。 是美国发病和死亡的主要原因。虽然肺移植是一种可行的 对于某些患者，5年生存率约为50%（主要是由于慢性 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， 捐献的肺和移植后短的移植物存活时间是主要的限制。因此，有一个 迫切需要了解慢性肺部疾病的病理生理机制， 设计创新的方法来修复或生物工程功能的肺。因此，这项建议将考验 假设肺细胞外基质（ECM）驱动适当的定位，分化， 它是肺细胞功能的重要组成部分，是正常肺修复和再生的关键因素。有一个长远的目标 再生一个功能性的人类肺，我们建议批判性地研究肺的组成成分， 本发明的目的在于开发脱细胞肺ECM并开发用于评估肺基质结构和功能的新工具。此外，本发明还 我们建议开发一种人肺生物反应器， 肺基质，同时维持生理通气和灌注。在需要解决的问题中， 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)我们能否开发出一种生物反应器 在进行机械通气的同时进行脱细胞化和随后再细胞化的人肺 和血管灌注在这个UOI应用中的工作将有助于肺的成功 再生联盟，因为我们将产生一个基本的和全面的了解肺 用作肺生长基质的基质。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调查结果。

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 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 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 UOl 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.