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Molecular Determinants of Lung Development

Executive Summary

Workshop Description

The National Heart, Lung, and Blood Institute (NHLBI) supports a strong portfolio of fundamental research on the determinants of lung development, which is contributing new information on the multiple key genes, molecules and signaling pathways that underlie the developmental process.

The Division of Lung Diseases (DLD) of NHLBI convened a workshop on September 7-8, 2011 to identify key knowledge gaps and priority areas in lung development research and to make recommendations for future research directions. This workshop sought to facilitate communications among diverse research groups, including scientists outside of the lung field, to encourage novel and systematic approaches to solving fundamental questions and to identify opportunities for advancing lung development research. Prior to the workshop, four working groups were organized to identify critical topics in multiple scientific areas. At the workshop, group leaders presented the consensus of views they compiled and facilitated the discussion of questions related to topics considered to be of high priority:

Environmental Impacts on Early Lung Development: This session focused on issues surrounding appropriate tissue samples to assess the impact of environmental insults on lung development and accessibility of these samples; generational and trans-generational conditions that are predictive of pulmonary disease; interactions between the macroenvironment and the pulmonary microenvironment; identity and role of fetal-derived lung factors that may be involved in signaling for parturition; and mechanisms through which the environment interacts with genes and chromatin that predispose the fetus to postnatal pulmonary disease.

Early Cell Fate and Morphogenesis: This panel raised a number of seminal topics, including: identifying temporal/spatial conditions that enable proper reactivation/inhibition of developmental pathways to promote lung repair and regeneration; employing developing lung to explore mechanisms and therapeutic options for lung repair and regeneration; the role of developmental pathways in lineage specification and differentiation; effects of epigenetic mechanisms on lung development and regeneration; role of defects in early morphological processes in influencing susceptibility to lung disease; identifying determinants of lung maturation events such as sacculation and alveologenesis; regulation of lung size and transition from growth to maturation; and coordination of heart and lung development.

Mechanisms of Lung Cell Differentiation: The issues discussed in this session included: the influence of cellular architecture in tissue morphogenesis and cell fate during lung differentiation and disease; the role of mechanotransduction in lung epithelial differentiation; functions of primary cilia in the airway epithelium and their relationship to motile ciliogenesis; role of cellular niche and extracellular matrix in regulating lung epithelial cell fate; epithelial-mesenchymal interactions in regulating cell differentiation; developmental basis of lung metaplasia in injury; role of protein degradation in lung development; and links between cellular phenotype and lung physiology.

Tissue Interactions in Lung Development: Topics of discussion included: genetic and epigenetic factors regulating and coordinating patterning of airways with that of lung blood vessels, lymphatics and neuronal innervations; identity and role of the relevant signaling pathways that govern tissue interactions; major factors impacting on these pathways, such as oxygenation, metabolic events, immune and inflammatory systems, endogenous progenitor cells, the microbiome, and mechanical factors related to the heart, blood vessels, musculoskeletal system, pleura, and placenta; development of pulmonary veins at the intersection of the heart and lung; development and function of lung lymphatics and their influence on lung maturation and function; roles of nerves in lung airway, vascular, and lymphatic development; pleural biology and potential functions of the pleura in developmental signaling and structural organization of the embryonic lung.

Recommendations

  1. Apply knowledge of developmental processes to investigate human lung development and disease and identify developmental pathways critically involved in human lung diseases. This will include, but not be limited to identifying clinical phenotypes that have components with developmental origins.
  2. Develop better experimental models to study the mechanisms of human lung diseases. Use these models and phenotypic screening tools to identify components of the disease process.
  3. Develop models and tools to study late lung development, including tracheobronchial, saccular and alveolar formation, cell interactions, pre- to postnatal transition, postnatal maturation and adaptability to the impact of environmental exposures.
  4. Characterize the mesodermal, neural and other non-endodermal lineages in the lung. Dissect individual lung mesenchymal cell lineages and determine the plasticity of mesenchymal phenotypes in response to injury.
  5. Determine how lung blood vessels and lymphatics develop, undergo maturation, are maintained, and respond to or contribute to lung pathology and disease.
  6. Study the impact of other organs and tissues (including placenta) on pre- and post-natal lung development. Identify the relationship of tissue interactions in the lung in human from development to disease.
  7. Characterize properties and patterning of the extracellular matrix and the microenvironment that promote regional differences in lung cellular differentiation, injury, repair, and regeneration.
  8. Fully exploit the advantages in lung research to study general biological processes, such as branching morphogenesis, lumen formation, establishment of host defense and unique microbiome, and interaction with the thymus and lymph nodes.
  9. Develop strategies for integration of systems biology approaches to decipher the mechanisms of developmental origins of lung diseases.
  10. Identify and study appropriate human cells and tissues obtained from developing/fetal/perinatal subjects, as well as leverage already available biospecimens from existing cohorts, in an effort to help define relevant disease pathways, biomarkers for prediction or treatment, and the relevance of animal and in vitro models.

Workshop Roster


Chairs

  • Edward Morrisey, Ph.D. University of Pennsylvania
  • Wellington V. Cardoso, M.D., Ph.D. Boston University
  • Robert Lane, M.D. University of Utah

Participants

  • Steven H. Abman, M.D. University of Colorado and The Children's Hospital,
  • Xingbin Ai, Ph.D. Boston University
  • Kurt H. Albertine, Ph.D., F.A.A.A. University of Utah
  • Richard Bland, M.D. Stanford University
  • Harold A. Chapman, M.D. University of California, San Francisco
  • William Checkley, M.D., Ph.D. The Johns Hopkins University
  • Jonathan Epstein, M.D. University of Pennsylvania
  • Christopher Kintner, Ph.D. The Salk Institute
  • Maya Kumar, Ph.D. Stanford University
  • Parviz Minoo, Ph.D. University of Southern California
  • Thomas Mariani, Ph.D. University of Rochester
  • Donald M. McDonald, M.D., Ph.D. University of California, San Francisco
  • Yosuke Mukoyama Ph.D. National Heart, Lung, and Blood Institute
  • Lawrence S. (Lance) Prince, M.D, Ph.D Vanderbilt University
  • Marlene Rabinovitch M.D. Stanford University
  • Jeffrey Reese, M.D. Vanderbilt University Medical Center
  • Janet Rossant Ph.D. The Hospital for Sick Children
  • Wei Shi, Ph.D. University of Southern California
  • Xin Sun, Ph.D University of Wisconsin-Madison
  • Zena Werb, Ph.D. University of California San Francisco
  • Jeffrey A. Whitsett, M.D. Cincinnati Children's Hospital Medical Center

NHLBI Staff

  • Qing "Sara" Lin, Ph.D., Division of Lung Diseases
  • Gail Weinmann, M.D., Division of Lung Diseases
  • Dorothy Gail, Ph.D., Division of Lung Diseases
  • Carol J. Blaisdell, M.D., Division of Lung Diseases
  • Charlene Schramm, Ph.D., Division of Cardiovascular Sciences
  • Weiniu Gan, Ph.D., Division of Lung Diseases

NIH CSR Staff

  • Ghenima Dirami, Ph.D., Division of Translational and Clinical Sciences

Last Updated: December 2011

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