To fulfill the promise of regenerative medicine in the lung, it will be necessary to identify and characterize the cell lineages that affect postnatal lun epithelial repair and to effectively control their maintenance, expansion, and differentiation into mature and functional epithelial cells. Asthma and COPD are chronic lung diseases which affect the bronchiolar airways of the lung and are leading causes of morbidity and mortality. Both diseases are thought to involve a chronic injury-repair-improper regeneration cycle that leads to the eventual breakdown of normal airway structure and function leading to loss of respiratory function. We hypothesize that epithelial progenitors within the bronchiolar airways and the pathways that regulate their expansion and differentiation are critical for proper airway repair and regeneration after both chronic and acute lung injury that occurs in lung diseases such as asthma and COPD. Given the immense clinical burden imposed by asthma and COPD, we believe a focus on repair and regeneration of bronchiolar epithelium will have a significant and direct impact on human health. Moreover, a focus on pathways that can be modulated using small molecule or "druggable" approaches would be beneficial for directly translating basic research findings to human therapy. We propose to leverage decades of experience by leading experts in lung development, stem cell biology, and pulmonary medicine to collaboratively harness novel technologies for expansion and differentiation of endogenous lung progenitors as well as those derived from induced pluripotent stem cells (iPSCs). By focusing on new findings in the investigators laboratories involving the epigenetic regulation of bronchiolar epithelial progenitors as well as novel techniques for generation of iPSCs, the Penn component of the Lung Repair and Regeneration Consortium (PennLRRC) will dramatically advance the field towards the ultimate goal of generating clinically relevant therapies for promoting lung repair and regeneration. The underlying thesis of the PennLRRC Consortium is that a sophisticated understanding of basic epigenetic mechanisms involving miRNA and Hdac pathways will be critical to optimally manipulate in vivo or generate ex vivo lung progenitors and their derivatives for clinical use.

Public Health Relevance

We will explore the roles for miRNA and Hdac pathways in lung regeneration and development as well as in the generation and differentiation of iPSCs for use in regenerative therapies in the lung. Since small molecule modulators of miRNA and Hdac pathways exist, we believe that investigation into how these pathways regulate lung regeneration will have an important impact on the development of new therapies for lung disease

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL110942-01
Application #
8221863
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
$734,623
Indirect Cost
$233,999
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Herriges, Michael J; Swarr, Daniel T; Morley, Michael P et al. (2014) Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development. Genes Dev 28:1363-79
Herriges, Michael; Morrisey, Edward E (2014) Lung development: orchestrating the generation and regeneration of a complex organ. Development 141:502-13
Kotton, Darrell N; Morrisey, Edward E (2014) Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med 20:822-32
Hogan, Brigid L M; Barkauskas, Christina E; Chapman, Harold A et al. (2014) Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15:123-38
Kadzik, Rachel S; Cohen, Ethan David; Morley, Michael P et al. (2014) Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape. Proc Natl Acad Sci U S A 111:12444-9
Chen, Bohao; Moore, Tamson V; Li, Zhenping et al. (2014) Gata5 deficiency causes airway constrictor hyperresponsiveness in mice. Am J Respir Cell Mol Biol 50:787-95
Miller, Mayumi F; Cohen, Ethan David; Baggs, Julie E et al. (2013) High throughput genomic screen identifies multiple factors that promote cooperative Wnt signaling. PLoS One 8:e55782
Morrisey, Edward E (2013) Balancing the developmental niches within the lung. Proc Natl Acad Sci U S A 110:18029-30
Peng, Tien; Tian, Ying; Boogerd, Cornelis J et al. (2013) Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor. Nature 500:589-92
Wang, Yi; Tian, Ying; Morley, Michael P et al. (2013) Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway. Dev Cell 24:345-58

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