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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL111016-01
Application #
8224021
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Blaisdell, Carol J
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$697,049
Indirect Cost
$133,088
Name
Yale University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Sun, Huanxing; Calle, Elizabeth; Chen, Xiaosong et al. (2014) Fibroblast engraftment in the decellularized mouse lung occurs via a *1-integrin-dependent, FAK-dependent pathway that is mediated by ERK and opposed by AKT. Am J Physiol Lung Cell Mol Physiol 306:L463-75
Ghaedi, Mahboobe; Mendez, Julio J; Bove, Peter F et al. (2014) Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor. Biomaterials 35:699-710
Tsuchiya, Tomoshi; Sivarapatna, Amogh; Rocco, Kevin et al. (2014) Future prospects for tissue engineered lung transplantation: decellularization and recellularization-based whole lung regeneration. Organogenesis 10:196-207
Klingberg, Franco; Hinz, Boris; White, Eric S (2013) The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol 229:298-309

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