The overall goal of this proposal is to better understand the role of Galphai2, a heterotrimeric guanine nucleotide binding (G) protein, in the regulation of pulmonary epithelial cell growth and development. G proteins transduce signals from serpentine receptors to intracellular effectors for an array of biological factors and numerous medically important pharmaceutical compounds. Recently it has been shown that a subgroup called pertussis toxin sensitive (PTX) G-proteins (Gi), particularly the Galphai2 isoform, plays a key role in growth and development. We found that a role of Galphai2 in lung growth is likely, since growth of fetal type II pneumocytes is inhibited by PTX. We confirmed that Galphai2 is expressed in fetal type II pneumocytes on the plasma membrane, a location consistent with its proposed interactions with growth factor receptors. We also found that expression of Galphai2 increases with the growth of these cells. Based on these observations, we hypothesize that Galphai2 is a key element in the regulation of the growth of fetal type II pneumocytes, and that Galphai2 in turn mediates it growth signal via the MAPK signaling cascade.
The specific aims of the proposal are: 1. To define the expression and distribution of Galphai2 in the developing lung and correlate this expression with activation of putative downstream kinases. 2. To define the role of Galphai2 in the growth of rat fetal type II pneumocytes in primary culture. The importance of MAPK in the growth effects of Galphai2 will be established. 3. To define the downstream intermediates between Galphai2 and MAPK in fetal type II pneumocytes. Serpentine receptors are amenable to pharmacological intervention. Thus understanding how G proteins regulate the growth and development of pulmonary epithelial cells has implications for the pathogenesis of cancer and the recovery from injuries such as ARDS (adult respiratory distress syndrome) and hyaline membrane disease.
| Ly, Ngoc P; Komatsuzaki, Katsumi; Fraser, Iain P et al. (2005) Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc Natl Acad Sci U S A 102:14729-34 |
