Reverse-engineering the lung

The Lung Development and Regeneration Lab, led by Dr. Douglas G. Brownfield, Ph.D., seeks to understand how the lung is constructed during development, repaired after injury and disrupted in disease. For each process, the lab's team first reverse-engineers in vivo then reconstructs in culture. In this manner, Dr. Brownfield and his team hope to understand the cellular and molecular basis of disease and repair as well as develop a rational approach to tissue and organ fabrication.

Tissues are complex combinations of cells and microenvironmental proteins arranged in a stereotyped architecture to perform critical physiologic processes. Most tissues throughout the body are assembled during development and, following injury, possess an intrinsic program capable of precise repair.

Diseases can occur when the programs of tissue construction and repair are defective, resulting in missing components and disrupted architecture. Such is often the case in the lung when bronchopulmonary dysplasia, chronic obstructive pulmonary disease and pulmonary fibrosis occur following disorganization of the tissue that mediates gas exchange (the alveolus). To effectively treat these diseases, it is imperative that we understand how the alveolus is constructed during development and repaired after injury.

To achieve this, the Brownfield lab reverse-engineers alveolar construction by:

  1. Enumerating the cellular and molecular parts
  2. Characterizing each part's assembly process in vivo
  3. Precisely reconstructing each process in culture

Using single-cell transcriptomics, genetically engineered mouse models and 3D organotypic culture, the Brownfield lab studies processes that underlie alveolar construction, beginning with one critical for first breath: fate specification of the two alveolar epithelial types (AT), the flat AT1 cells that provide the surface of gas exchange and the cuboidal AT2 cells that secrete surfactants preventing alveolar collapse.

Beyond mapping the cellular and transcriptional process at single-cell resolution, Dr. Brownfield's lab hopes to identify key regulators of specification and patterning of the critical components that comprise the alveolus. Moreover, the lab is applying their findings in the adult alveolus to:

  1. Determine whether identified processes are reinitiated in injury as well as disrupted in disease
  2. Develop novel therapeutic approaches to promote alveolar repair