This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Normal lung growth and development during fetal life are critical for extrauterine survival. Mechanical forces generated in utero by repetitive breathing movements and by fluid distension are essential to mammalian lung development. Previous studies from our laboratory showed that mechanical stretch, simulating fetal breathing movements, induces fetal type II cell maturation. Our Preliminary Studies have revealed important functions for mitogen-activated protein kinase (MAPK) signal cascades and the actin cytoskeleton in stretch-induced type II cell differentiation. We also have identified potential roles for heterotrimeric G-proteins and specific receptor tyrosine kinases, RTKs (i.e., the epidermal growth factor and insulin-like growth factor-I receptors [EGFR, IGF-IR]) as mechanosensors during alveolar development. The long-range goal of these studies is to understand cell and molecular mechanisms that transduce mechanical stretch signals into a lung differentiation program. We will test the central hypothesis that cell surface mechanosensors activate the ERK MAPK pathway and actin cytoskeletal remodeling to promote fetal epithelial cell differentiation. First, we will test the hypothesis that the EGFR and IGF-IR function as 'mechanosensors' in developing distal pulmonary epithelial cells and we will determine whether stretch-induced transactivation by G-proteins is required for the mechanosensor properties. We then will test the following hypotheses: (a) Interactions between specific RTKs (EGFR, IGF-IR) and G-protein coupled receptors (GPCRs) activate ERK-dependent signaling and permit stretch-induced type II cell maturation; and (b) the proximal effector Raf-1 plays a key role in conveying mechanical signals into the ERK cascade. Finally, we will determine if direct contacts between ERK pathway effector proteins andactin-associated proteins are required. We will focus on the actin-associated protein alpha-actinin. These studies will incorporate complementary biochemical, genetic and molecular imaging techniques.
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