The first specific aim is based on preliminary data that indicates that the MEK inhibitor U0126 reduces ERK-1/2 activity, induces mesenchymal apoptosis, and dramatically inhibits branching morphogenesis in fetal lung explants. To demonstrate that ERK-1/2 signaling plays a critical role in fibroblast apoptosis and lung development/branching morphogenesis I propose to rescue ERK-1/2 signaling with an adenoviral construct encoding the a constitutively activated MEK gene. The second specific aim is based on my preliminary data in which I have shown that ERK-3 expression is developmentally regulated during fetal lung development and is expressed in the P19 embryonic carcinoma cell line. I will try to determine the role of ERK-3 in development by cloning the ERK-3 gene into an adenoviral vector and both inhibiting and over expressing the ERK-3 gene in fetal lung explants and P19 cells. The third specific aim will examine the mechanism of nitrofen-induced apoptosis and pulmonary hypoplasia and the mechanisms of antioxidant rescue of nitrofen-induced pulmonary hypoplasia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL069684-02
Application #
6622291
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (20))
Program Officer
Colombini-Hatch, Sandra
Project Start
2002-01-01
Project End
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
2
Fiscal Year
2003
Total Cost
$53,944
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Aidlen, Jeremy T; Nazarey, Pradeep P; Kinane, T Bernard et al. (2007) Retinoic acid-mediated differentiation protects against nitrofen-induced apoptosis. Birth Defects Res B Dev Reprod Toxicol 80:406-16
Kling, David E; Brandon, Kirra L; Sollinger, Christina A et al. (2006) Distribution of ERK1/2 and ERK3 during normal rat fetal lung development. Anat Embryol (Berl) 211:139-53
Kling, D E; Aidlen, J T; Fisher, J C et al. (2005) Nitrofen induces a redox-dependent apoptosis associated with increased p38 activity in P19 teratocarcinoma cells. Toxicol In Vitro 19:1-10