The proposal is comprised of an organized training program in an outstanding academic environment and a focused project to enable the candidate to develop as an independent physician-scientist. Training/Environment: This application focuses on the effects of mechanical forces on fetal lung development and extends the candidate's prior research training. The mentors and academic environment are unparalleled, providing coursework, seminars, and broad expertise in developmental lung biology, tissue mechanotransduction, and intracellular signaling, and includes an advisory committee from these disciplines. Research Plan: Integration of stimuli from static stretch (due to secretion of fetal lung fluid) and cyclic stretch (from fetal breathing) results in a mix of type I and type II cells in the developing fetal lung. Yet supraphysiologic stretch from postnatal ventilator therapies is deleterious, contributing to decreased alveolization and bronchopulmonary dysplasia. Animal studies suggest that stretch is important for lung cell growth and differentiation; static distention favors a type I cell phenotype, whereas cyclic stretch promotes a type II cell phenotype. The mechanisms by which stretch induces changes in cell phenotype are poorly understood. We hypothesize that: 1) static stretch of the human alveolar epithelium triggers expression of type I alveolar epithelial cell markers, whereas cyclic stretch triggers expression of type II cell markers; and 2) these effects are mediated through stimulation of the actin cytoskeleton and the Rho-Rho kinase pathway of Rho GTPase second messengers, but are independent of extracellular matrix composition. The proposed studies will utilize unique in vitro models of human fetal alveolar epithelial cells and an equibiaxial deformation stretch device to 1) Determine the effects of static and cyclic stretch on human alveolar epithelial cell phenotype, 2) Establish the role of the cytoskeleton and Rho GTPases in stretch-induced phenotype changes in human alveolar epithelial cells, and 3) characterize the contributions of the extracellular matrix to this process.
| Foster, Cherie D; Varghese, Linda S; Gonzales, Linda W et al. (2010) The Rho pathway mediates transition to an alveolar type I cell phenotype during static stretch of alveolar type II cells. Pediatr Res 67:585-90 |
