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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL111016-03
Application #
8601879
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
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$594,064
Indirect Cost
$122,094
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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Fiore, Vincent F; Strane, Patrick W; Bryksin, Anton V et al. (2015) Conformational coupling of integrin and Thy-1 regulates Fyn priming and fibroblast mechanotransduction. J Cell Biol 211:173-90
Sontake, Vishwaraj; Shanmukhappa, Shiva K; DiPasquale, Betsy A et al. (2015) Fibrocytes Regulate Wilms Tumor 1-Positive Cell Accumulation in Severe Fibrotic Lung Disease. J Immunol 195:3978-91
White, Eric S (2015) Lung extracellular matrix and fibroblast function. Ann Am Thorac Soc 12 Suppl 1:S30-3

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