The proposal in this application outlines a five-year training program for the development of a career as a physician-scientist in cardiopulmonary biology. The candidate is an Instructor of Pediatrics and a pediatric cardiologist at the Children?s Hospital of Philadelphia. The proposed research will be carried out under the mentorship of Dr. Edward E. Morrisey, Ph.D., a leader in the field of cardiopulmonary development. Dr. Morrisey has trained numerous young investigators including several physician-scientists who currently hold academic appointments. An advisory committee has been assembled to provide expertise in pulmonary and cardiovascular biology in addition to career guidance from well-established to newly appointed independent investigators. The research environment has been carefully selected to include exposure to two institutions allowing access to extensive resources, core facilities, and intellectual guidance. In addition, the candidate will be participating in didactic courses and numerous professional development seminars to help ensure adequate training for independence. Together, this provides a unique and ideal environment for the candidate to develop the skills to transition to an independent physician-scientist in the cardiopulmonary field. I have identified a subpopulation of Wnt signaling-responsive type 2 alveolar epithelial cells (AT2s), called Axin2+ AT2s or AT2sAxin2, which exhibit enhanced stem cell characteristics during alveologenesis (Frank DB et al. Cell Reports. 2016 Nov 22;17(9):2312-2325). In addition, the transcriptome of Axin2 AT2s are highly enriched for genes that are essential for vascular development and extracellular matrix production and interactions. The goal of this proposal is to not only further characterize this progenitor cell population in the alveolus but also examine the mechanism by which it orchestrates alveolar epithelial and endothelial growth during generation and regeneration of the alveolus. Therefore, the proposal will address these processes with two overriding aims: 1) Examine the regulation of alveolar epithelial cell self-renewal by Wnt ligand secretion; and 2) Identify and delineate the role of Wnt signaling and Wnt signaling-responsive alveolar progenitor cell populations in the epithelial-vascular niche of the developing and regenerating alveolus. ! The training program and research proposed in this application will provide critical tools, skills, and scientific expertise to become a physician-scientist in the pediatric cardiopulmonary field, a relatively understudied and underfunded area of pediatric research. There is no cure for pediatric PH and developmental lung diseases such as BPD. Thus, the identification and characterization of alveolar epithelial progenitor or stem cells could provide novel targets for therapy and lung growth.

Public Health Relevance

With the improved care for premature infants, there has been an increase in the number of premature newborns with bronchopulmonary dysplasia (BPD), a lung disease marked by a disruption in the normal development of the lung. I have identified a group of lung epithelial stem cells, called Axin2+ type 2 alveolar epithelial cells (AT2s), and my proposed studies will attempt to harness the potential of the Axin2+ AT2s and learn how they orchestrate lung generation and regeneration. These findings will provide insight into a relatively understood disease in addition to providing novel cellular targets for therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL140129-01
Application #
9432059
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Colombini-Hatch, Sandra
Project Start
2018-01-19
Project End
2022-12-31
Budget Start
2018-01-19
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104