PHA/ATS Partnership Grant Winner 2006
Xinqi Wu, PhD
Children’s Hospital Boston
“Hypoxic regulation of BMP signaling and the role of Id1 in the development of pulmonary hypertension”
Term: January 1, 2006 – December 31, 2007
Summary of Research Project:
Hypoxic regulation of BMP signaling and the role of Id1 in the development of pulmonary hypertension
Primary pulmonary hypertension (PPH) is a fatal disorder characterized by excessive growth of blood vessel cells in the lungs, resulting in narrowing of vessels and increased blood pressure in the lungs followed by heart failure. Genetic studies have linked PPH to heterozygous mutations in the type 2 bone morphogenetic protein receptor (BMPR) gene. These mutations could cause disruption of BMPR signaling, resulting in increased growth and inhibition of apoptosis of vascular cells. A second hit is also required for the disease to be manifested. Hypoxia is a particularly important stimulus for pulmonary hypertension (PH) and has been used in several animal models to understand the pathogenesis of this disease. The molecular mechanisms for PPH and hypoxia-induced PH remain poorly understood. We found that hypoxia suppressed BMPR signaling in cultured human pulmonary artery smooth muscle cells (HPASMC), resulting in suppression of BMP-stimulated Id1 gene activation. Id1 attenuated proliferation and promoted apoptosis of HPASMC. Thus, we hypothesize that the suppression of Id1 may cause increased growth and inhibition of apoptosis of HPASMC, significantly contributing to PH development. We proposed to investigate Id1 expression in hypoxic lungs of mice and the role of Id1 in cell cycle progression, proliferation, apoptosis and migration, processes underlying vascular remodeling. We will identify additional hypoxia-regulated BMP target genes. These studies will enhance our understanding of PPH pathogenesis and may lead to the identification of molecules that play a critical role in PPH development and thus might be used as targets for therapeutic intervention.
- 1980-1984 Wuhan University, Wuhan, China, B.S., Biology
- 1984-1987 Shanghai Jiaotong University, Shanghai, China, M.S., Molecular Biology
- 1990-1993 University of Wurzburg, Wurzburg, Germany, PhD, Biochemistry
- Massachusetts Institute of Technology, Cambridge, MA
- Tufts University, Medford, MA 1995-1997
- University of Pennsylvania, Philadelphia, PA 1997-1998
Positions and Employment
- 1987-1990 Instructor, Zhongshan University, Guangzhou, China
- 1998-2001 Instructor, Brigham and Women's Hospital/Harvard Medical School, Boston, MA
- 2001- Instructor, Children’s Hospital/Harvard Medical School, Boston, MA
- 1994 Faculty Award of the School of Chemistry and Pharmacy of Wurzburg University, Germany
Other Published Articles
- Wu X, Stella Kourembanas. Hypoxia suppresses bone morphogenetic protein mediated Id1 gene activation in human pulmonary artery smooth muscle cells (abstract). American Thoracic Society Annual Meeting 2004. May 2004, Orlando, FA.
- Wu X, Chang MS, Mitsialis SA, Kourembanas S. Hypoxia regulates bone morphogenetic protein signaling through C-terminal binding protein 1. Circ Res. 2006; 99:240-247.