This project provides a carefully organized training program and a focused research project that will enable the candidate to pursue a career as an independent pulmonary physician-scientist. Training/Environment: The candidate has had previous basic science training as a graduate student, and subsequently completed medical school, residency and subspecialty clinical training. The program in this application involves a new field for the candidate, focusing on basic mechanisms in developmental biology of the pulmonary circulation. The scientific mentors and laboratory provide for a complete background in a new field of science, with emphasis on molecular biology skills not included in prior training. The academic environment provides important seminar series and selected graduate-level courses, and an already established advisory committee will continue to mentor the applicant. Finally, his limited clinical activities will focus on evaluation and treatment of pulmonary vascular diseases, thus establishing a basis for future complimentary basic science and clinical investigation. Research Plan: Little is known of the molecular mechanisms of pulmonary vascular morphogenesis despite the importance of vascular derangements in numerous lung diseases. Pulmonary vascular development involves de novo differentiation of stem cells into endothelial networks (vasculogenesis) and the outgrowth of new from previously formed vessels (angiogenesis). Cell differentiation in numerous systems is controlled by members of the Notch family of molecules and recent findings implicate a Notch ligand, Jagged-1, in vascular morphogenesis and pulmonary vascular development. The studies in this proposal test the hypothesis that Jagged-1 functions in the molecular control of endothelial differentiation during vasculogenesis and pulmonary vascular development. Preliminary data establish an in vitro model of vasculogenesis demonstrating inducible expression of both endothelial specific markers and Jagged-1 in association with formation of vascular-like tubes, as well as the expression of Jagged-1 in the developing murine fetal lung.
Three specific aims define the role of Jagged-1 in: 1) an in vitro model of vasculogenesis, 2) pulmonary vascular formation in an established model of lung bud branching morphogenesis and 3) pulmonary vascular development in vivo. This work will provide important insight into the basic developmental biology of the pulmonary vasculature.
| Kawut, Steven M; Taichman, Darren B; Archer-Chicko, Christine L et al. (2003) Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 123:344-50 |
| Taichman, Darren B; Loomes, Kathleen M; Schachtner, Susan K et al. (2002) Notch1 and Jagged1 expression by the developing pulmonary vasculature. Dev Dyn 225:166-75 |
