DR. ROBYN J. BARST PEDIATRIC PH RESEARCH AND MENTORING FUND GRANT WINNER 2015

David Brian Frank, MD, PhDDavid Brian Frank, MD, PhD

Instructor/T32 Grant Trainee, Cardiology
The Children’s Hospital of Philadelphia, University of Pennsylvania
Title: “Wnt signaling progenitor cells in late lung development, regeneration, and repair”
Term: December 1, 2015- November 30, 2016

The Matthew and Michael Wojciechowski Pediatric PH Research & Mentoring Grant

This Barst Fund Award is made possible through a generous donation to PHA from Ms. Betty Lou Wojciechowski in honor of her two late sons, Matthew and Michael, who lost their battles to PH.

Summary of Research Project:

Lung disease in the newborn period can be a significant health burden and can lead to serious complications. 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 airspace and blood vessels. This decrease in blood vessels often results in elevated blood pressures in the lung causing pulmonary hypertension (PH). Currently, there is no cure for PH or BPD. Therefore, new ideas for therapy are warranted. Because the lung airway and blood vessels rely on each other for development, we have been examining the lung distal airway niche for lung stem cell populations that are critical for normal lung development. We have identified a subpopulation of specialized lung distal airway epithelial cells, called Axin2+ type 2 alveolar epithelial cells (AEC2s) that have the Wnt growth factor pathway activated. The Wnt growth factor pathway is involved in stem cell maintenance and differentiation in many different organs in the body. Preliminary studies suggest that Axin2+ AEC2s have enhanced stem cell properties. Using novel cell culture models, we have shown that these cells can form “lung organoids”, a rudimentary distal airway sac. Compared to all other alveolar epithelial cells, the Axin2+ AEC2s form increased numbers of the lung organoids that can also survive in cell culture for a longer period of time. Interestingly, we are able to take the normal distal airway cells and treat them with a chemical that turns on the Wnt pathway resulting in similar stem cell abilities seen in the specialized Axin2+ AEC2s. We have also been able to manipulate the normal type 2 alveolar epithelial cells to behave like Axin2+ AEC2s by modifying genes in mice. When we turn on the Wnt pathway in normal AEC2s in mice, they proliferate more and give rise to more AEC2s. We will design experiments to modify a gene that turns on the Wnt pathway to turn normal AEC2s into Axin2+-like AEC2s following lung injury in newborn mice. We will also turn on the Wnt pathway in the different neighboring cells of AEC2s to examine their ability to support repair of the injured lung. We hypothesize that this newly identified cell population and its neighbors have the potential for reactivation following lung injury to regenerate lost lung tissue including lung blood vessels and prevent the development of PH in BPD.

Curriculum Vitae

Education/Training

1997: BS in Biochemistry from the University of Nebraska-Lincoln
2006: PhD in Cell & Developmental Biology from Vanderbilt University School of Medicine, Nashville, TN
2009: MD in Medicine from Vanderbilt University School of Medicine, Nashville, TN
2011: Pediatrics Recovery at The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
2015: Pediatric Cardiology Fellowship at The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
Current: Research Fellow at the University of Pennsylvania

Honors/Awards

1997: Howard Hughes Medical Institute Undergraduate Summer Research Award-University of Nebraska-Lincoln
1998-2000: Predoctoral Cancer Research Training Award, National Cancer Institute
2005: Genzyme Keystone Conference Scholarship, Keystone Conference on TGF-beta and Disease
2001-2009: Microbes and Defense Academic Society, Vanderbilt University School of Medicine
2009: Richard B. Johnston Jr. Award in Pediatrics, Vanderbilt University School of Medicine
2011: CHOP Research Day Poster Award Winner
2013: Fellow’s Award 6th International Conference Neonatal and Childhood Pulmonary Vascular Disease
2014: Finalist presenter at The Neonatal Cardiopulmonary Biology Young Investigators’ Forum
2015: Society for Pediatric Research Fellow Research Award
2015: CHOP Research Day Poster Award Winner

Research Support

NHLBI T32 HL007915-16 10/1/2013-current
Training in Molecular Therapeutics for Pediatric Cardiology (RJ Levy, PI) Role:  Research Fellow/Trainee

Selected Publications

  1. Wurthner JU, Frank DB, Felici A, Green HM, Cao Z, Schneider MD, McNally JG, Lechleider RJ, Roberts AB.  2001.  Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone. J Biol Chem.  276(22):19495-502.  PMID: 11278302.
  2. Parks WT, Frank DB, Huff C, Renfrew Haft C, Martin J, Meng X, de Caestecker MP, McNally JG, Reddi A, Taylor SI, Roberts AB, Wang T, Lechleider RJ.  2001.  Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases. J Biol Chem.  276(22):19332-9.  PMID: 11279102.
  3. Frank DB, Abtahi A, Yamaguchi DJ, Manning S, Shyr Y, Pozzi A, Baldwin HS, Johnson JE, de Caestecker MP.  2005.  Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ Res.  PMID: 16100039.
  4. Frank D, Johnson J, de Caestecker M. 2005.  Bone morphogenetic protein 4 promotes vascular remodeling in hypoxic pulmonary hypertension. Chest. 128(6 Suppl):590S-591S.  PMID: 16373851.
  5. Frank DB, Lowery J, Anderson L, Brink M, Reese J, de Caestecker M.  2008.  Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol.  294(1):L98-109.   PMID: 18024717.
  6. Anderson L, Lowery JW, Frank DB, Novitskaya T, Jones M, Mortlock DP, Chandler RL, de Caestecker MP.  2010.  Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol.  298(3):R833-42.   PMCID: PMC2838658.
  7. Frank DB, Crystal MA, Morales DL, Gerald K, Hanna BD, Mallory GB, Rossano JW. 2015.  Trends in Pediatric Pulmonary Hypertension Related Hospitalizations in the United States from 2000-2009.  Pulm Circ.In Press (http://www.jstor.org/stable/10.1086/681226)
  8. Frank DB, Hanna BD. 2015.  Pulmonary Arterial Hypertension Associated with Congenital Heart Disease and Eisenmenger Syndrome:  Current Practice in Pediatrics.  Minerva Pediatr.67(2): 169-85. PMCID: PMC438210