The alveolar region of the mammalian lung is a complex, precisely structured tissue required for the primary functions of the respiratory system, gas exchange and tissue oxygenation. Damage to the alveolar epithelium plays a central role in human lung diseases including Acute Respiratory Distress Syndrome (ARDS), a prevalent, high impact clinical disorder that affects up to 5% of mechanically ventilated patients in the developed world. The mortality rate of ARDS approaches 40%, and the recovery for ARDS survivors is arduous, with a substantial burden of multi-system disability continuing 5 or more years following hospitalization. Critically, while many ARDS survivors recover lung function, a subset of patients develops persistently abnormal pulmonary function, imaging evidence of pulmonary scarring, and pulmonary symptoms even years after ARDS. To date, no data exists regarding the mechanisms that guide ARDS recovery. A key requirement for developing strategies to improve recovery after ARDS and promote lung regeneration is to understand progenitor populations in the lung, and their specific roles in the complex, regionalized nature of regeneration after injury. We have found a distinct group of Wnt-responsive AT2 cells. These cells comprise a distinct progenitor sublineage, which we call AEPs (Axin2+ Alveolar Epithelial Progenitors). AEPs are capable of generating both AT1 and AT2 cells in vivo and in vitro, are stable for 9 months during alveolar homeostasis, and expand rapidly to regenerate a majority of the alveolar epithelium after diffuse alveolar damage. Importantly, we have identified an AEP-enriched cell surface receptor that marks AEPs in both mouse and human lung, which has allowed functional validation of human AEPs as a progenitor lineage. The ability to directly compare AEPs from mouse and human has provided specific insight into possible upstream signals and downstream effectors required for AEP function. The scientific objective of this proposal is to directly evaluate the requirement and role for several such candidate factors in AEP biology during lung regeneration, with a specific emphasis on the combinatorial role of Wnt and Fgf signals in promoting AEP function.
The Aims of the proposal are 1) Define the requirement for Wnt signaling in AEP biology during alveolar regeneration and 2) Determine the function of FGFR2 signaling and ETS transcription factors in AEPs. The other crucial objective of this proposal is to provide for a structured, focused training plan to allow the primary investigator to develop an advanced armamentarium of research techniques in regenerative biology and allow for a successful transition to independence.

Public Health Relevance

When patients recover after lung illnesses, including pneumonia, influenza infection, or more severe lung injuries requiring a ventilator, the lung must heal. The mechanisms by which this healing occurs are unknown, and no medications exist to help lung healing when the process does not occur correctly. We have found a new lung stem cell that is important in lung healing after injury, and are working to identify signals that control the function of this cell to provide opportunities for new therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL140178-03
Application #
9975881
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Kalantari, Roya
Project Start
2018-07-21
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229